KR20140145597A - Omega-3 fatty acid ester compositions - Google Patents

Abstract

Described herein are compositions comprising at least one omega-3 fatty acid ester and at least one surfactant, wherein the composition forms micelles upon contact with an aqueous medium. Also provided is a pharmaceutical composition comprising at least one omega-3 fatty acid ester and at least one surfactant, wherein the at least one omega-3 fatty acid ester forms micelles upon contact with an aqueous medium, wherein the bioavailability of the at least one omega- There is provided a method of administering to a subject a composition that is substantially independent of an effect. The composition is useful for treating cardiovascular conditions or disorders in a subject and for reducing the side effects associated with the ingestion of omega-3 fatty acid esters. In addition, various dosage forms for administering the composition and the use of the composition in functional foods are described. Also provided herein is a kit having instructions for how to administer the composition.

Description

Omega-3 fatty acid ester compositions < RTI ID = 0.0 >

Related application

The present application claims priority from U.S. Provisional Patent Application No. 61 / 618,161 filed on March 30, 2012.

Background technology

According to the World Health Organization (WHO) data sheet on cardiovascular disease (CVD), CVD is the leading cause of death worldwide [Data Sheet No. 317, September 2012, access (http: // www. who.int/mediacentre/factsheets/fs317/en/index.html, January 31, 2013). WHO estimates that in 2008 about 17,300,000 people, representing 30% of global deaths, died from CVD. Of these deaths, approximately 7,300,000 people were due to coronary heart disease (CHD), and approximately 6,200,000 people were caused by stroke. In addition, WHO estimates that by 2030 almost 25 million people will die from CVD, mainly heart disease and stroke. The Global Burden of Disease Study estimates that developing countries accounted for 3,500,000 of the 6,200,000 global deaths caused by CHD in 1990 [Murray CJL and Lopez AD. The Global Burden of Disease A Comprehensive Assessment of Mortality and Disability from Disease, Injuries and Risk Factors in 1990 and Projected to 2020. Boston, MA Harvard University Press; 1996]. These estimates assume that these countries will account for 7,800,000 of the 11,100,000 deaths caused by CHD in 2020. Developed countries are also affected by CHD. For example, in the USA and Europe, CHD remains the single largest cause of death and disability. In 2005, CHD caused approximately one death per 5 deaths in the USA [Heron MP, et. al. Deaths preliminary data for 2006. Natl. Vital. Stat. Rep. 2008; 56: 1-52.]. According to the Centers for Disease Control and Prevention, this is the leading cause of death in the United States. Approximately 37% of those who have a coronary event in one year will die from it. Although a major reduction in CVD-related mortality was achieved in Europe, CVD still accounts for 54% of total female deaths and 43% of male total deaths.

CVD is associated with many risk factors. Of these risk factors, hyperlipidemia (eg hypertriglyceridemia) and hypercholesterolemia are important indicators of CVD. Dietary supplements, omega-3 fatty acid esters, such as ethyl esters of EPA and DHA, and nutraceuticals and prescribed drugs are now being used for the treatment of CVD, particularly for the reduction of increased triglycerides.

However, the administration of dietary supplements, medicated foods, and prescribed medicaments, including omega-3 fatty acid esters, presents considerable challenges. For example, commonly used dietary supplements, omega-3 fatty acid esters, pharmaceutical preparations and prescribed medicaments have variable absorption and efficacy upon oral administration. In particular, the compositions in common have a pronounced "food effect" with poor absorption upon ingestion during fasting or low fat meals. The absorption of omega-3 fatty acid esters improves upon ingestion with fat foods, which is due in part to the presence of bile salts released from above, which aids in the absorption of omega-3 fatty acid esters.

In order to overcome low absorption, it is possible to administer a composition having a large amount of omega-3 fatty acid esters to the patient, but there are practical limitations to this approach due to the side effects commonly associated with such compositions. Due to the oxidative degradation of omega-3 fatty acid esters that occur over time, they can have an unpleasant aftertaste after administration, especially in large doses. In addition, trim and stomach upset are unpleasant side effects associated with omega-3 fatty acid ester use. Omega-3 fatty acid esters tend to float on top of the liquid contents above and form a layer that prevents the passage of small gas droplets. If enough gas is produced to overcome the surface tension of the oil layer, the person will trim. Trims often include fish tastes and odors.

Thus, side effects associated with the administration of commonly used compositions including omega-3 fatty acid esters (e.g., sensitivity to food effects, high doses to achieve efficacy and resulting aftertaste, unpleasant odors, and trims) Is significantly reduced.

Practicing a healthy lifestyle can reduce the incidence of CVD, but a new therapeutic approach to managing CVD is needed. This new approach may involve discovering new drugs or improve conventional drugs used to treat CVD. However, the discovery of new drugs is costly without certainty of the final success. Thus, there is a need to develop new or more efficient ways of delivering commonly used drugs with a proven safety and efficacy profile. Therefore, there is a need for improved compositions comprising omega-3 fatty acid esters, e. G., Ethyl esters of EPA and DHA, which are less sensitive to food effects and achieve higher efficacy at lower doses. Ideally, these improved compositions will minimize or eliminate unpleasant odors and / or unpleasant aftertaste and / or patient trim. These improved compositions with reduced side effects will improve patient compliance and more effectively treat risk factors associated with cardiovascular disease.

In all embodiments provided herein, not all compositions contain omega-3 free fatty acids. In certain embodiments herein, compositions are provided that include EPA and DHA esters with one or more surface active agents. In certain embodiments, the ratio of EPA ester to DHA ester is greater than 2: 1 to less than 3.4: 1. Certain embodiments provide a ratio of EPA ester to DHA ester of from about 2: 1 to about 3.4: 1. In certain embodiments herein, compositions are provided that comprise at least one omega-3 fatty acid ester and at least one surfactant. In certain embodiments, the omega-3 fatty acid esters are selected from the group consisting of hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosa- Hexanoic acid, tetracohexanoic acid, tetracohexanoic acid, or a combination thereof. Certain embodiments provide a composition comprising an ethyl ester derivative of the omega-3 fatty acid ester optionally together with one or more surface active agents, one or more terpenes, one or more antioxidants, or a combination thereof. In addition, certain embodiments provide a blend of different omega-3 fatty acid esters in a ratio of about 2: 1 to about 3.4: 1. Other embodiments provide a ratio of greater than 2: 1 to less than 3.4: 1. Typically, the ratio is about 2.4: 1. Certain embodiments are directed to various conditions that can be treated by administering an omega-3 fatty acid ester in the composition described herein, optionally including one or more surface active agents, one or more terpenes, one or more antioxidants, or a combination thereof, Or a method of treating a disorder. The compositions described herein are found in presently available compositions, including omega-3 fatty acid esters, which can render a human subject unable to follow the dosage regimen required to treat a condition or disorder treatable by administering an omega-3 fatty acid ester Thereby minimizing several side effects. In certain embodiments, the bioavailability of omega-3 fatty acid esters is substantially the same when administered as a particular composition as described herein, when administered to a subject in need of such administration, with or without food (I. E. Substantially independent of the food effect).

Accordingly, certain embodiments provide a pharmaceutical composition comprising at least one omega-3 fatty acid ester and at least one surfactant, wherein said at least one omega-3 fatty acid ester occupies at least about 40% (wt / wt) .

Particular embodiments are directed to a composition comprising at least one of hexadecatrienoic acid, alpha-linolenic acid, stearidic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosahexanoic acid, docosahexanoic acid, Pentanoic acid, and tetracohexaenoic acid, and a first omega-3 fatty acid ester selected from the group consisting of hexadecatrienoic acid,? -Linolenic acid, stearidonic acid, eicosapentaenoic acid, eicosapentaenoic acid, A second omega-3 fatty acid ester selected from the group consisting of niacosapentaenoic acid, docosahexanoic acid, docosahexanoic acid, tetracosapentaenoic acid and tetracohexaenoic acid, 2 omega-3 fatty acid esters are different from each other, the ratio of the first omega-3 fatty acid ester to the second omega-3 fatty acid ester is more than 2: 1 to 3.4: 1 (the first omega- (Omega-3 fatty acid ester), the combined first and second omega-3 fatty acid esters constitute about 40% (wt / wt) or more of the composition, Lt; RTI ID = 0.0 > pharmaceutically < / RTI >

Certain embodiments provide for the use of one or more omega-3 fatty acid esters. Typically, the omega-3 fatty acid ester is an ethyl ester.

Certain embodiments include one or more omega-3 fatty acid esters and one or more terpenes, wherein the at least one omega-3 fatty acid ester occupies at least about 40% (wt / wt) Wherein the pharmaceutical composition is substantially free of active ingredients. In certain embodiments, the at least one omega-3 fatty acid ester comprises about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%. Terpenes are typically d-limonene, but not necessarily. In certain other embodiments, such compositions comprise natural orange oil.

Certain embodiments include EPA ethyl and DHA ethyl esters and one or more terpenes, wherein the ratio of EPA: DHA is about 2.4: 1 and the combined EPA and DHA ethyl esters comprise about 40% (wt / wt) To about 95% (wt / wt). In certain embodiments, the combined EPA and DHA ethyl esters comprise about 40% (wt / wt) of the composition. Terpenes are typically d-limonene, but not necessarily. In certain other embodiments, such compositions comprise natural orange oil.

In embodiments involving substantially pure d-limonene, d-limonene is about 95% to about 98% pure. In certain embodiments, the substantially pure d-limonene is at least 95%, 96%, 97% or 98% pure.

In certain embodiments, the omega-3 fatty acid ester is selected from the group consisting of one or more EPA esters, one or more DHA esters, or combinations thereof, and comprises one or more surfactants. In certain embodiments, the one or more EPA esters and the one or more DHA esters are substantially pure. In addition, certain embodiments provide a composition that comprises about 2: 1 to about 3.4: 1 ratio of one or more EPA esters and one or more DHA esters and is substantially free of other active ingredients other than omega-3 fatty acid esters. Compositions comprising different proportions are also described. In addition, certain compositions may not contain natural orange oil or d-limonene. In certain embodiments, omega-3 fatty acid esters comprise more than 40% of the composition. Typically, the omega-3 EPA and DHA esters are ethyl esters. Certain compositions described herein form micelles in an aqueous medium and have no food effect. Certain compositions are substantially free of food effects when administered with or without food. Also provided herein are methods of treating cardiovascular conditions or disorders using the compositions described herein. The compositions described herein minimize or eliminate side effects in comparison to administering compositions of the prior art. In addition, packaged compositions or kits of omega-3 fatty acid esters comprising one or more unit dosage forms are provided with instructions for use of the compositions.

Thus, in one or more embodiments, a composition comprising a weight to weight ratio of greater than about 2: 1 to about 3.4: 1 (EPA: DHA) of one or more EPA esters and one or more DHA esters and one or more surfactants, EPA and DHA esters comprise from about 40% to about 85% by weight of the composition. In certain such embodiments, the combined EPA and DHA ethyl ester accounts for about 50% (wt / wt) of the composition.

In one or more other embodiments, the composition comprises a weight to weight ratio of about 2: 1 to about 3.4: 1 (EPA: DHA) of one or more EPA esters and one or more DHA esters and one or more surface active agents, Wherein the ester comprises from about 40% to about 85% by weight of the composition. In certain such embodiments, the combined EPA and DHA ethyl ester accounts for about 50% (wt / wt) of the composition.

In one or more other embodiments, comprises a weight to weight ratio of greater than 2: 1 to about 3.4: 1 (EPA: DHA) of one or more EPA esters and one or more DHA esters and one or more surfactants, Wherein the DHA ester comprises from about 40% to about 85% by weight of the composition. In certain such embodiments, the combined EPA and DHA ethyl ester accounts for about 50% (wt / wt) of the composition.

In one or more other embodiments, comprises a weight to weight ratio of greater than 2: 1 to about 3.4: 1 (EPA: DHA) of one or more EPA esters and one or more DHA esters and one or more surfactants, A pharmaceutical composition is provided wherein the DHA ester comprises from about 40% to about 85% by weight of the composition and wherein the composition is administered to a human subject in need of such administration with or without food, wherein the DHA ester is substantially independent of the food effect . In certain such embodiments, the combined EPA and DHA ethyl ester accounts for about 50% (wt / wt) of the composition.

In one or more embodiments, the compositions described herein comprise substantially pure one or more EPA esters and / or one or more DHA esters.

In one or more embodiments, the compositions described herein are made essentially of one or more EPA esters and / or one or more DHA esters.

In certain embodiments, either or each of the EPA and DHA esters constituting the composition is an ethyl ester.

In certain embodiments, the compositions described herein comprise a substantially pure EPA ethyl ester and / or a substantially pure DHA ethyl ester.

In certain embodiments, the compositions described herein are essentially composed of a substantially pure EPA ethyl ester and / or a substantially pure DHA ethyl ester.

In certain embodiments, the ratio of EPA and DHA esters comprising the composition is about 2.4: 1 (EPA ester: DHA ester).

Certain embodiments provide compositions comprising from about 0.1% to about 5% (wt / wt) natural orange oil of the composition. In embodiments involving natural orange oil, the natural orange oil is present at about 1.6% (wt / wt) of the composition. Certain other embodiments include from about 0.1% to about 5% substantially pure d-limonene. In embodiments involving substantially pure d-limonene, d-limonene is present at about 1.5% (wt / wt) of the composition.

In certain embodiments, the pharmacological effects of the compositions described herein are substantially independent of the food effect upon administration to the subject.

In one or more embodiments, a) at least 80% by weight of the composition comprises (all-Z omega-3) -5,8,11,14,17- Eicosapentaenoic acid (EPA) and (all-Z omega-3) -4,7,10,13,16,19-docosahexanoic acid (DHA); b) (all-Z omega-3) -6,9,12,15,18-henicosapentaenoic acid is present in an amount of at least 1% by weight; and c) at least one surfactant. These compositions may optionally further comprise from about 0.1% to about 5% (wt / wt) natural orange oil or from about 0.1% to about 5% (wt / wt) substantially pure d-limonene of the composition. Natural orange oil is typically present at about 1.6% (wt / wt) of the composition and d-limonene is typically present at about 1.5% (wt / wt) of the composition.

In at least one embodiment, a) at least 80% by weight of the composition is composed of omega-3 fatty acids; b) at least 80% by weight of the total fatty acid content of the composition is (all-Z omega-3) -5,8,11,14,17-eicosapentaa in a weight ratio of EPA: DHA of 1: 2 to 2: (EPA) and (all-Z omega-3) -4,7,10,13,16,19-docosahexanoic acid (DHA); c) the omega-3 fatty acids other than EPA and DHA are present in an amount of at least 1.5% by weight of the total fatty acids; c) a mixed-fatty acid composition for treating or preventing one or more of a plurality of risk factors for CVD, comprising one or more surfactants. These compositions may optionally further comprise from about 0.1% to about 5% (wt / wt) natural orange oil or from about 0.1% to about 5% (wt / wt) substantially pure d-limonene of the composition. Natural orange oil is typically present at about 1.6% (wt / wt) of the composition and d-limonene is typically present at about 1.5% (wt / wt) of the composition.

In one or more embodiments, a) at least 80% by weight of the composition comprises (all-Z omega-3) -5,8,11,14,17-Eicosane in a weight ratio of EPA: DHA of 1: 2 to 2: (EPA) and (all-Z omega-3) -4,7,10,13,16,19-docosahexanoic acid (DHA); b) at least 3% by weight of the composition is composed of omega-3 fatty acids other than EPA and DHA having 18, 20, 21 or 22 carbon atoms; and c) at least one surfactant. These compositions may optionally further comprise from about 0.1% to about 5% (wt / wt) of natural orange oil or from about 0.1% to about 5% (wt / wt) of substantially pure d-limonene of the composition . Natural orange oil is typically present at about 1.6% (wt / wt) of the composition and d-limonene is typically present at about 1.5% (wt / wt) of the composition.

In at least one embodiment, a) at least 90% by weight of the composition is composed of long chain polyunsaturated omega-3 fatty acids; b) at least 80% by weight of the composition comprises (all-Z omega-3) -5,8,11,14,17-eicosapentaenoic acid (EPA) in a weight ratio of EPA: DHA of from 1: 1 to 2: And (all-Z omega-3) -4,7,10,13,16,19-docosahexanoic acid (DHA), wherein the EPA comprises from 40% to 60% by weight of the composition , DHA comprises from 25% to 45% by weight of the composition; c) at least 4.5% by weight of the composition is composed of omega-3 fatty acids other than EPA and DHA having 18, 20, 21 or 22 carbon atoms; d) from 1 to 4% by weight of the composition is composed of (all-Z omega-3) -6,9,12,15,18-hemicosapentaenoic acid; e) comprises at least one surface-active agent; f) A pharmaceutical mixed-fatty acid composition is provided wherein the composition is in an oral dosage form and comprises an effective amount of a pharmaceutically acceptable antioxidant. These compositions may optionally further comprise from about 0.1% to about 5% (wt / wt) natural orange oil or from about 0.1% to about 5% (wt / wt) substantially pure d-limonene of the composition. Natural orange oil is typically present at about 1.6% (wt / wt) of the composition and d-limonene is typically present at about 1.5% (wt / wt) of the composition.

It should be noted that in all embodiments involving compositions described herein, the sum of all components making up the composition does not exceed 100%.

In certain embodiments, a pharmaceutical or pharmaceutical composition comprising EPA and DHA in a weight to weight ratio of from about 3.5: 1 to about 5: 1, and at least one surfactant, wherein the combined EPA and DHA is greater than 84 wt% / RTI > These compositions may optionally further comprise from about 0.1% to about 5% (wt / wt) natural orange oil or from about 0.1% to about 5% (wt / wt) substantially pure d-limonene of the composition. Natural orange oil is typically present at about 1.6% (wt / wt) of the composition and d-limonene is typically present at about 1.5% (wt / wt) of the composition.

Certain embodiments comprise a composition comprising at least about 96% by weight of ethyl eicosapentaenoate (ethyl-EPA), one or more surface active agents, and substantially no docosahexaenoic acid (DHA) or esters thereof . These compositions may optionally further comprise from about 0.1% to about 5% (wt / wt) natural orange oil or from about 0.1% to about 5% (wt / wt) substantially pure d-limonene of the composition. Natural orange oil is typically present at about 1.6% (wt / wt) of the composition and d-limonene is typically present at about 1.5% (wt / wt) of the composition.

In one or more embodiments, a method is provided for treating the following disorders: cognitive impairment including cognitive impairment as a result of metabolic syndrome, macular degeneration, omega-3 deficiency, surgery or traumatic brain injury (e.g., , Major depression, suicide, postpartum depression, inflammation, primary sclerosing cholangitis, borderline personality disorder in women, breast cancer, non-alcoholic fatty liver disease, and cognitive and behavioral improvement in children. These conditions or disorders can be treated by administering the compositions described herein to a subject, usually a human, in need of such administration.

In one or more embodiments, there is provided a method of treating a subject suffering from cardiovascular disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of omega-3 fatty acid ester and at least one surface active agent, There is provided a method of treating one or more cardiovascular conditions or disorders.

In one or more embodiments, one or more cardiovascular conditions or disorders include, but are not limited to, hypertension, hyperlipidemia, hypertriglyceridemia, atherosclerosis, transient ischemic attack, systolic dysfunction, diastolic dysfunction, , Acute myocardial infarction (AMI), acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), angina pectoris, unstable angina pectoris (UA), stable angina pectoris (SA) ), Myocardial infarction, congestive heart failure, dilated congestive cardiomyopathy, hypercardiomyopathy, restrictive cardiomyopathy, pulmonary heart disease, arrhythmia, valvular heart disease, endocarditis, pulmonary embolism, venous thrombosis, peripheral vascular disease and peripheral arterial disease A method of treating cardiac and vascular disorders is provided. The method comprises administering to a subject in need thereof a therapeutically effective amount of a composition as described herein.

In at least one embodiment, a method of treating hypertension and / or hyperlipidemia is provided.

In at least one other embodiment, a method of treating hypertriglyceridemia is provided.

In certain embodiments, the total amount of TG in the human subject's blood having a TG above 150 mg TG (triglyceride) per dL of serum at the beginning of the dosing regimen is within about 30 days after administration of a particular embodiment of the composition described herein %.

In one or more other embodiments, there is provided a method of treating a patient in need of such treatment comprising administering to a human subject one or more embodiments of a composition described herein comprising a therapeutically effective amount of an omega-3 fatty acid ester, A method of treating a human subject having the above TG is provided.

Also provided is an embodiment packaged as a kit, with instructions on how the composition described herein may be used to treat a cardiovascular condition or disorder.

In certain embodiments, the surfactant is selected from the group consisting of one or more nonionic surfactants, cationic surfactants, anionic surfactants, zwitterionic surfactants, or combinations thereof.

In certain embodiments, the surfactant is selected from the group consisting of one or more anionic surfactants, one or more non-ionic surfactants, and combinations thereof.

In certain embodiments comprising one or more surface active agents, the at least one surface active agent has a hydrophilic-lipophilic balance (HLB) of about 8.0.

In certain embodiments comprising one or more surface active agents, the surface active agent can be a non-ionic surface active agent selected from the group consisting of one or more polysorbates, one or more poloxamers, and combinations thereof.

In certain embodiments, the at least one surfactant comprises polysorbate present in the composition at about 15% wt / wt to about 31% wt / wt. In certain embodiments, the polysorbate is polysorbate 80.

In certain other embodiments, the at least one surface active agent comprises a poloxamer present in the composition at about 0.1% to about 5% wt / wt.

In certain embodiments, the compositions described herein comprise polysorbate 80 and poloxamer pluronic F87 [(HO (C ₂ H ₄ O) ₆₄ (C ₃ H ₆ O) ₃₇ (C ₂ H ₄ O) ₆₄ H ≪ / RTI >

In certain embodiments, the composition further comprises one or more antioxidants. In this embodiment, the at least one antioxidant is selected from the group consisting of tocopherol, tocotrienol, or a combination thereof. In this embodiment, tocopherol, tocotrienol, or a combination thereof is present at from about 0.01% to about 5% by weight of the composition. In certain such embodiments, tocopherol, tocotrienol, or a combination thereof is present in an amount ranging from about 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5% May be present in an amount of from 0.1% by weight, 0.8% by weight, 0.9% by weight, 1% by weight, 1.5% by weight, 2% by weight, 2.5% by weight, 3% by weight, 3.5% by weight, 4% by weight, 4.5% . In certain such embodiments, tocopherol, tocotrienol, or a combination thereof is present at about 0.4% by weight relative to the composition. In certain embodiments, the tocopherol, tocotrienol, or combination is present at about 0.4% by weight of the composition. In certain embodiments further comprising one or more antioxidants, the antioxidant is about 0.4% by weight tocopherol of the composition.

In certain embodiments, the composition is self-micellised in an aqueous medium. In certain other embodiments, the aqueous medium is water. In certain other embodiments, the aqueous medium has an acidic pH. In certain other embodiments, the aqueous medium is 0.1 N HCl.

In certain embodiments, the compositions described herein are self-micellized in an aqueous medium and the micelle has a diameter of from about 1 [mu] m to about 10 [mu] m. In certain embodiments, the compositions described herein are self-micellized in an aqueous medium at an acidic pH and the micelle has a diameter of from about 1 [mu] m to about 10 [mu] m. In certain other embodiments, the compositions described herein are self-micellised in 0.1 N HCl and the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. In certain embodiments, the micelle has an average diameter of about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 μm.

In certain embodiments, the compositions described herein may be administered to a subject in need of such administration with or without food, and the bioavailability of the omega-3 fatty acid esters constituting the composition is substantially independent of the food effect .

Certain embodiments provide compositions that minimize or eliminate one or more side effects from administration of the compositions of the present disclosure as compared to administration of a composition comprising omega-3 fatty acid esters substantially free of surface active agents. In other embodiments, non-limiting examples of side effects include, but are not limited to, reflux, frequent trimming, GERD, hypertrophy, increased intestinal gas, fishy taste, acute respiration, fishy smell, nausea, diarrhea, do.

In certain embodiments, the compositions described herein comprise d-limonene or natural orange oil. Such a composition may minimize or eliminate one or more side effects from administration of the compositions of the present disclosure as compared to administration of a composition comprising an omega-3 fatty acid ester substantially free of d-limonene or natural orange oil. In other embodiments, non-limiting examples of side effects include, but are not limited to, reflux, frequent trimming, GERD, hypertrophy, increased intestinal gas, fishy taste, acute respiration, fishy smell, nausea, diarrhea, do.

In certain embodiments, the composition described herein is administered to a patient in need of treatment comprising administering a therapeutically effective amount of a compound selected from the group consisting of individuals having about 155 to about 199 mg of TG per dL of serum, about 200 to about 499 mg of TG per dL of serum and about 500 mg or more per dL of serum, When administered to a selected human subject, it reduces the subject's serum TG level by about 20% or more.

A particular embodiment of the composition described herein is a non-omega-3 fatty acid ester lipid-lowering agent selected from the group consisting of a cholesterol absorption inhibitor, a bile acid sequestrant / resin, a statin, a niacin and a derivative, an MTP inhibitor, a fibrate and a CETP inhibitor May be administered to a subject in need of such administration.

In certain embodiments, the compositions described herein may reduce the total amount of TG in high blood triglyceride human subject serum having a TG of at least 150 mg per dL of serum at the beginning of the dosing regimen by about 20% or more within about 30 days of administration of the composition have.

In one or more embodiments, the compositions described herein may be administered orally or parenterally in a suitable dosage form. When administered orally, the compositions described herein are typically, but not necessarily, administered in the form of a gel or liquid capsule.

In certain other embodiments, a composition is provided herein that comprises from about 40% to about 85% by weight of the composition, of at least one EPA ester and at least one DHA ester and at least one surfactant in a ratio of greater than 2: 1 to less than 3.4: A particular embodiment of the described composition is administered at least about 0.5 g / day. Typically, the ester is an ethyl ester and the at least one surfactant is polysorbate 80, pluronic F87 or a combination thereof, but this is not necessarily so. In certain such embodiments, the combined EPA and DHA ethyl ester accounts for about 50% (wt / wt) of the composition. Optionally, the composition may further comprise substantially pure d-limonene or natural orange oil.

In certain other embodiments, a composition comprising ethyl eicosapentaenoic acid (ethyl-EPA) and one or more surface active agents and substantially free of docosahexaenoic acid (DHA), wherein the ethyl-EPA is present in a total omega- A particular embodiment of the composition described herein constituting at least about 96% by weight of the ester is administered at least about 4 g / day. In certain embodiments, such compositions may further comprise natural orange oil or substantially pure d-limonene.

Certain embodiments provide the use of the compositions described herein in the manufacture of a medicament for the treatment of cardiovascular disease or disorder. In certain embodiments, the cardiovascular disease or disorder is hyperlipidemia. In certain other embodiments, the cardiovascular disease or disorder is hypercholesterolemia. In certain embodiments, the cardiovascular disease or disorder is hypertriglyceridemia.

Certain embodiments provide the use of the compositions described herein in the manufacture of a medicament for the treatment of cardiovascular disease or disorder. In certain embodiments, the cardiovascular disease or disorder is hyperlipidemia. In certain other embodiments, the cardiovascular disease or disorder is hypercholesterolemia. In certain embodiments, the cardiovascular disease or disorder is hypertriglyceridemia.

In certain embodiments, administration of a composition as described herein provides for a serum concentration of at least about 20 nmol / mL of at least one EPA ester and at least one DHA ester in about 4 hours after administration of a particular embodiment in a human subject .

Also provided is a kit comprising a composition of omega-3 fatty acid esters in one or more unit dosage forms with instructions for use of the dosage form. In certain embodiments, the dosage forms described herein may be packaged as blister packs or bottles with instructions for use of the dosage forms. For example, the instructions may be provided as a package insert or directly on a blister pack, on a label attached to a bottle, or on a secondary packaging that a blister pack or bottle has been provided to a human subject. The instructions can include, for example, the number of doses, administration of a dosage form administered with or without food, cardiovascular conditions or disorders benefiting from administration of the active ingredient and dosage form comprising the dosage form.

In certain embodiments, a kit is provided wherein a particular dosage form, including the compositions described herein, can be packaged with other non-omega-3 fatty acid ester lipid lowering agents. The kit (s) may contain one or more unit dosage forms comprising a non-omega-3 fatty acid ester lipid-lowering agent and one or more unit dosage forms of certain embodiments of the compositions described herein, .

Certain embodiments provide a functional food (s) for treating and / or preventing CVD comprising the compositions described herein.

Certain embodiments provide a method of treating CVD by administering a functional food comprising a composition as described herein.

Certain embodiments provide functional food (s) comprising the compositions described herein and methods of treating hypertriglyceridemia in a human subject.

1 is a photomicrograph of an embodiment. As described herein, a composition comprising micelles was prepared, placed between slides and cover slip, and magnified 40x with a Nikon Model Trinocular Head and a Spot RT3 digital camera. The diameters of representative micelles were measured.
Figure 2 is a schematic flow diagram of a process for making one embodiment of the composition described herein.
Figure 3 is a schematic flow diagram of a process for making a gel mass for encapsulating one embodiment of the composition described herein.
Figure 4 is a schematic flow diagram of an encapsulation process for preparing a dosage form comprising one embodiment of the composition described herein.

Certain aspects, modes, embodiments, variations and features of the present invention relate to compositions comprising omega-3 fatty acid esters and to methods of using such compositions comprising high concentrations of omega-3 fatty acid esters Are described herein in various levels to provide a further understanding of the method. In certain embodiments, EPA esters and DHA esters are present in specific weight ratios (%) and relative amounts. As noted, these compositions have beneficial effects on certain risk factors for CVD, including lowering serum triglycerides and serum cholesterol.

Justice

The term "composition (s)" or "formulation (s)" as used herein includes therapeutic and dietary compositions including, but not limited to, dietary supplements, pharmaceutical formulations or pharmaceutical formulations. In addition, the term compositions, dietary supplements, pharmaceutical formulations, and pharmaceutical formulations are used interchangeably herein.

The term "EPA" as used herein refers broadly to (5Z, 8Z, 11Z, 14Z, 17Z) -Ecosa-5,8,11,14,17-pentenoic acid or Refers to derivatives thereof.

As used herein, the term "DHA" refers broadly to alkyl esters such as (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -docosa-4,7,10,13,16,19 - < / RTI > hexanoic acid or derivatives thereof.

The term "micelle (s) " as used herein refers to a collection of molecules that are assembled into a nearly spherical core / shell structure and suspended in the aqueous phase. The orthomorphic micelles in the aqueous solution form aggregates having a hydrophilic "head" region upon contact with the surrounding solvent and / or upon contact with the polar regions of the one or more surfactant (s) and isolate the hydrophobic region at the center of the micelle. Micelles are almost spherical.

As used herein, the term " self-micelleizing "refers to the process in which micelles are formed in an aqueous medium without the introduction of energy, including stirring or shearing.

The term "aqueous medium " as used herein includes, but is not limited to, water alone; Refers to any solution or suspension comprising water, including phosphate buffered saline pH 7.4, sprites, apple juice, G-2 fruit punch, and chocolate milk. In certain embodiments, the aqueous medium comprises one or more fluids having an acidic pH. In certain other embodiments, the aqueous medium comprises a biological fluid, such as, but not limited to, gastric acid. In another embodiment, the aqueous medium comprises simulated gastric acid comprising 0.1 N HCl.

The term "free fatty acid" as used herein refers to one or more polyunsaturated fatty acids that are not modified or have no other group attached thereto.

The term "ester" as used herein refers to a substitute for another substituent of a hydrogen in a carboxylic acid group of a polyunsaturated fatty acid molecule. Exemplary esters are known to those skilled in the art and a discussion of this can be found in Higuchi, T. et al., Prodrugs as Novel Delivery Systems , Vol. 14, ACS Symposium Series, Bioreversible Carriers in Drug Design , Ed. Edward B. Roche, Amer. Pharma. Assoc., Pergamon Press (1987), and Protective Groups in Organic Chemistry , McOmie ed., Plenum Press, New York (1973), each of which is incorporated herein by reference in its entirety). Examples of common esters include methyl, ethyl, trichloroethyl, propyl, butyl, pentyl, tert-butyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, monoglyceride, diglyceride, triglyceride .

The term "monoglyceride " as used herein refers to a fatty acid chain covalently bonded to a glycerol molecule via an ester linkage, such as a DHA or EPA molecule. The term "diglyceride " as used herein refers to a fatty acid chain covalently bonded to a glycerol molecule via an ester linkage, such as DHA or EPA, wherein the glycerol molecule is DHA or EPA via one additional ester linkage Lt; RTI ID = 0.0 > additional < / RTI > fatty acid chain. The term "triglyceride " as used herein refers to a fatty acid chain covalently bonded to a glycerol molecule via an ester linkage, such as DHA or EPA, wherein the glycerol molecule is either DHA or EPA via two additional ester bonds, Lt; RTI ID = 0.0 > additional < / RTI > fatty acid chains.

The term "terpene " as used herein refers to a large and diverse class of organic compounds produced by various plants, particularly coniferous trees. When terpenes are chemically modified, for example, by oxidation or rearrangement of the carbon skeleton, the resulting compounds are generally referred to as "terpenoids" (e.g., carbons). Terpen and terpenoids are major constituents of many types of plant and flower essential oils.

As used herein, the terms " alpha -tocopherol, "" tocopherol "and" vitamin E "refer to a set of tocopherols and tocotrienols, respectively, fat soluble vitamins having antioxidant properties.

The term "antioxidant" as used herein refers to a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a material to an oxidant. Oxidation reactions can produce free radicals. These radicals can then initiate a chain reaction. If a chain reaction occurs in a cell, it can damage the cell or cause death. Antioxidants stop these chain reactions by eliminating free radical intermediates and inhibit other oxidation reactions. They stop the chain reaction by oxidizing themselves, and these antioxidants are often reducing agents, such as thiol, ascorbic acid or polyphenols. Exemplary antioxidants include, but are not limited to, rosemary oil, ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotene, melatonin, ubiquinol (coenzyme Q), alpha -tocopherol (vitamin E), ascorbyl palmitate, Butylated hydroxytoluene, monothioglycerol, and meta-sodium bisulfite.

As used herein, a pharmaceutically acceptable "carrier" refers to any material suitable as a vehicle for delivering a molecule or composition to a suitable in vivo absorption site. Examples of such carriers include, but are not limited to, water, phosphate buffered saline (PBS), Ringer's solution, dextrose solution, serum-containing solution, Hank's solution and other aqueous physiologically-balanced solutions.

Pharmaceutically acceptable "preservatives " as used herein include, but are not limited to, potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, For example, ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.

As used herein, "colorant" provides coloration to the composition or dosage form. Such colorants include food grade dyes.

The term "subject " as used herein refers to mammals including, but not limited to dogs, cats, horses, cows, pigs, sheep, goats, chickens, rodents, primates or humans. Subjects include animals such as domestic pets such as dogs and cats, agricultural livestock such as cows, horses, pigs, chickens, etc., laboratory animals such as mice, rats, rabbits and the like But is not limited thereto. A human subject can be a child, an adult, or an elderly person. A human subject can be male or female.

The terms "cardiovascular disease" and "cardiovascular condition ", as used herein, include, for example, hypertension, hyperlipidemia, hypertriglyceridemia, atherosclerosis, transient ischemic attack, systolic dysfunction, diabetic dysfunction, (AMI), acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), angina pectoris, unstable angina pectoris (UA), stable angina pectoris (SA) Myocardial infarction, myocardial infarction, congestive heart failure, dilated congestive cardiomyopathy, hypercardiomyopathy, restrictive cardiomyopathy, pulmonary heart disease, arrhythmia, valvular heart disease, endocarditis, pulmonary embolism, venous thrombosis, peripheral vascular disease and peripheral arterial disease Includes vascular system disorders.

For example, hypertriglyceridemia is a condition associated with cardiovascular disease in which the fasting serum concentration of triglyceride is at least 150 mg / dL. Blood concentrations may be increased from a moderately high level of 200 mg / dL to 500 mg / dL, or, in severe cases, to more than 500 mg / dL. The American Heart Association recommends that triglyceride levels be increased from "normal" (<150 mg / dL), "elevated" (150-199 mg / dL), "high" (200-499 mg / dL) / dL). It will be clear to those skilled in the art that the distinction of high triglycerideemia may vary from country to country. For example, the Canadian and European guidelines have indicated that the fasting serum triglyceride levels below 1.7 mmol / L are "desirable", 1.7-2.2 mmol / L are "borderline", 2.3-6.6 mmol / L are "high" / L is recommended as "very high". It will also be appreciated by those skilled in the art that the composition of elevated serum triglyceride levels may vary by age and gender.

As used herein, an "effective amount" or "therapeutically effective amount ", as used in a composition as described in some embodiments herein, refers to an amount sufficient to achieve the desired therapeutic and / or prophylactic effect, Or reduce the symptoms associated therewith. The amount of the composition to be administered to a subject, particularly to a subject in need of the composition, may depend on the type and severity of the disease and the characteristics of the subject, for example, general health, age, sex, body weight and tolerance to the drug. A person of ordinary skill in the art will be able to determine appropriate dosages according to these and other factors. Typically, an effective amount of the composition described herein may be sufficient to achieve a therapeutic or prophylactic effect.

As used herein, the terms " dosage unit ", "unit dose ", and" dosage unit "refer to a portion of a composition comprising an effective amount of an active agent suitable for single administration to provide or contribute to a therapeutic effect. Such dosage units may be administered one to several times per day (i.e., 1 to about 10 times, 1 to 8 times, 1 to 6 times, 1 to 4 times, or 1 or 2 times), or a number of times &Lt; / RTI &gt;

The term "food effect &quot;, as used herein, refers to the activity of an active substance or a composition thereof, such as a tablet, capsule or liquid, when administered to a subject orally, C _max (maximum plasma concentration), and / or T _max (time to maximum concentration) to the same value when the same composition was administered in the fasted state. The food effect F is calculated as follows:

F = (Y _meal -Y _fasting ) / Y _fasting

In this formula,

Y _meals and Y _fasting are observations of AUC, C _max or T _max in the meal and fasting states, respectively. The food effect F is generally established when F is greater than 1.

In general, the term "AUC" or "area under the plasma concentration-time curve" relates to the total amount of active material measurable in the systemic circulation after single dose administration. The AUC is a mathematical and visual representation of the amount of aggregation of the active in the system throughout the predetermined period of time. Changes in AUC need not necessarily reflect changes in the total amount of active material that is absorbed, but may reflect changes in the kinetic of distribution, metabolism, and excretion. Thus, the term AUC, as used herein, refers to the total amount of omega-3 fatty acids measurable in the systemic circulation following a single dose administration of any of the compositions described herein.

The term " T _max "or" time of peak concentration "refers to the period of time required to achieve the peak plasma concentration of the active substance after a single dose administration. Thus, the term _{Tmax as} used herein refers to the period of time required to achieve the peak plasma concentration of the omega-3 fatty acid ester after single dose administration of any of the compositions described herein.

The term " _Cmax " or "peak concentration" is the highest concentration of active that is achieved in plasma. Thus, the term _{Cmax as} used herein refers to the maximum concentration of omega-3 fatty acid ester after single dose administration of any of the compositions described herein.

As used herein, the term " substantially unrelated to food effect "or" substantially free of food effect "means that after oral administration of any of the compositions described herein, the effect of the food on absorption is substantially eliminated (For example, F is about 0). In other words, the bioavailability of omega-3 fatty acid esters is substantially the same regardless of whether the composition described herein is administered with or without food as measured by log-modified AUC. In certain embodiments, the pharmacological effect of administering the compositions described herein is substantially independent of the food effect.

As used herein, the term "reduced food effect" refers to a substantial decrease in the food effect on absorption after oral administration of any of the compositions described. In certain embodiments, the compositions described herein have a reduced food effect.

As used herein, the term " simultaneously with food "or" administered in a meal state "refers to administration from about 30 minutes before meals to about 1 hour after meals.

The various modes of treatment or prevention of a medical condition as described herein are intended to mean "substantial" or " substantially "including complete but also less complete treatment or prevention and some biologically or medically related results being achieved do. A subject in need of treatment, e.g., a human subject, refers to a subject that requires treatment of a predetermined disease state or that requires prophylactic treatment (i. E. Prevention) of such disease state.

The term " about "or" approximately "as used herein is intended to encompass within the allowable error range for a particular value measured by a person skilled in the art, which may depend in part on the manner in which the value is measured or determined, it means. Where a particular value is recited in the specification and claims, unless otherwise indicated, the term " about "means within an acceptable range of tolerances for a particular value.

The term "active substance (s) "," active ingredient (s) ", "active agent" or "pharmaceutically active ingredient" Or a chemical entity intended to have a direct effect in restoring, correcting or modifying physiological function in a subject.

The term "functional food" as used herein refers to any edible or foodable food or dietary ingredient (e.g., juice, milk, yogurt, butter, margarine, baking products) that is fortified or enhanced with any of the compositions described herein. . The functional food may be, for example, a solid, a liquid, a semi-solid or a combination thereof. The term "functional food" also includes food and drinkable nutritional supplements.

The term "hydrophilic-lipophilic balance" or "HLB" as used herein refers to the relative affinity of a substance or composition for aqueous and oily phases. The HLB value may be calculated based on methods and equations known to those skilled in the art, for example, those described in U.S. Patent 5,585,192. The material or composition generally has an average HLB of from about 6 to about 20. Hydrophilic-lipophilic balance values can be measured, for example, by various formulas or experimental methods provided in U.S. Patent No. 5,585,192.

The term "substantially pure" as used herein means at least 90% pure.

Pharmaceutical composition

In one or more embodiments, there is provided a composition comprising at least one omega-3 fatty acid ester and at least one surfactant and self-micellised upon contact with an aqueous medium. In certain embodiments, the at least one omega-3 fatty acid ester comprises from about 40% (wt / wt) to about 85% (wt / wt) of the composition. In certain embodiments, the at least one omega-3 fatty acid ester is present in an amount of about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% Respectively.

In certain embodiments, the compositions described herein self-micelle in 0.1 N HCl. It is well accepted that 0.1 N HCl (simulated gastric juice) serves as a substitute for the pH of the stomach contents. Thus, without being bound by theory, it is believed that the compositions described herein are capable of self-micelle formation at the stomach or small intestine. In certain embodiments, the compositions described herein deliver omega-3 fatty acid esters more efficiently and effectively through the small intestine when administered with or without food.

Certain embodiments provide for the use of omega-3 fatty acid esters. Thus, in one embodiment, one or more (5Z, 8Z, 11Z, 14Z, 17Z) -Ecosa-5,8,11,14,17-pentenoic acid (EPA) esters; Or one or more (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -docosa-4,7,10,13,16,19-hexanoic acid (DHA) esters; Or a combination thereof and provides a composition that has a ratio of EPA ester to DHA ester of greater than 2.0: 1.0 to 3.4: 1.0 or less and is substantially free of other active ingredients other than omega-3 fatty acid esters. In certain embodiments, the omega-3 fatty acid ester in the composition comprises an omega-3 fatty acid ethyl ester. In certain embodiments, EPA and DHA esters comprise at least about 40% to about 95% (wt / wt) of total omega-3 fatty acid ester in the composition. In certain embodiments, EPA and DHA esters are present in the composition at about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% 90% or 95% (wt / wt).

(5Z, 8Z, 11Z, 14Z, 17Z) -Ecosa-5,8,11,14,17-pentenoate to alkyl (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -docosa-4,7,10,13,16,19-hexaenoate (EPA: DHA) was effective in reducing the TG concentration in serum . In certain embodiments, the EPA and DHA esters comprise more than 40% of the total omega-3 fatty acid esters of the composition. In certain embodiments, EPA and DHA esters are present in the composition at about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% 90% or 95%. Also provided is a composition having an omega-3 fatty acid ester comprising greater than about 2.0: 1.0 to about 3.4: 1.0 (EPA: DHA ester) is formulated with one or more surface active agents to produce a composition that self- It can be done. Micelles are generally uniformly spherical and stable, providing absorption of omega-3 fatty acid esters substantially free of any food effect. Based on observations that the compositions described herein are self-micellising in 0.1 N HCl, the compositions described herein are also believed to be self-micellising in the stomach or small intestine. In certain embodiments, such compositions provide an advantageous drug delivery profile for omega-3 fatty acid esters.

In certain embodiments, the compositions described herein, including EPA and DHA esters, eliminate many of the side effects commonly associated with the administration of omega-3 fatty acid esters. Thus, compositions described herein, including EPA and DHA esters, do not produce a bad smell and / or do not produce an unpleasant aftertaste and do not cause a trim in a patient. In yet another embodiment, one or more (5Z, 8Z, 11Z, 14Z, 17Z) -Ecosa-5,8,11,14,17-pentenoic acid (EPA) esters; Or one or more (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -docosa-4,7,10,13,16,19-hexanoic acid (DHA) esters; Or a combination thereof, wherein the composition has a ratio of EPA ester to DHA ester of greater than about 2.0: 1.0 to about 3.4: 1.0, and at least one surfactant, wherein the EPA ester, DHA ester, -3 &lt; / RTI &gt; fatty acid esters. In certain embodiments, the omega-3 fatty acid ester in the composition comprises an omega-3 fatty acid ester. In certain embodiments, EPA and DHA esters comprise at least about 40% to about 95% (wt / wt) of total omega-3 fatty acid ester in the composition. Thus, in certain embodiments, EPA and DHA esters are present in the composition at about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% %, 90% or 95% (wt / wt).

In certain embodiments, the ratio of EPA fatty acid ester to DHA ester is greater than 2.0: 1.0 to 3.4: 1.0 or less. In certain embodiments, the ratio of EPA ester to DHA ester is from about 2.0: 1 to about 3.4: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.0: 1.0 to about 3.0: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.0: 1.0 to about 2.7: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.0: 1.0 to about 2.5: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.0: 1.0 to about 2.4: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.1: 1.0 to about 2.3: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.1: 1.0 to about 2.2: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is about 2.4: 1.0.

In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.0: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.1: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.15: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.2: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.3: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.4: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.5: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.6: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.7: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.8: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 2.9: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 3.0: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 3.1 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 3.2: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 3.3: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is about 3.4: 1.0.

In certain embodiments, the compositions described herein comprise one or more of the following hexadecatrienoic acids ("HTA" or 16: 3 (n-3), or all-Z-7,10,13-hexadecatrienoic acid) ("SDA" or 18: 4 (n-3), or all-Z-9,12,15-octadecatrienoic acid), a-linolenic acid (ETE) or 20: 3 (n-3) or all-Z-11,14,17 (ETA) or 20: 4 (n-3), or all-Z-8,11,14,17-eicosatetraenoic acid), eicosapentaa ("EPA" or 20: 5 (n-3) or all-Z-5,8,11,14,17-eicosapentaenoic acid), heneicosapentaenoic acid ("HPA" (n-3) or all-Z-6,9,12,15,18-heneicosapentaenoic acid), docosa-pentaonic acid ("DPA" or clupanodonic acid or 22: 5 all-Z-7,10,13,16,19-docosapentaenoic acid); (DHA) or 22: 6 (n-3) or all-Z-4,7,10,13,16,19-docosahexanoic acid), tetracosapentaenoic acid (24: (n-3) or all-Z-9,12,15,18,21-tetracosapentaenoic acid), tetracosahexanoic acid (nishin acid or 24: 6 (5Z, 8Z, 11Z, 14Z, 17Z) - tetracohexanoic acid ester. In certain embodiments provided herein, the ester is selected from the group consisting of (4Z, 7Z, 10Z, 13Z, 16Z, 19Z) -dokosa-4,7,10,13,16,19-dicarboxylic acid ester of Eicosapenta-5,8,11,14,17-pentenoic acid (EPA) In certain embodiments, the ester is a single omega-3 fatty acid ester In certain embodiments, the ester is a single omega-3 fatty acid ester In certain embodiments, the ester is a single omega-3 fatty acid ester In certain embodiments, -3 fatty acid esters, such as those recited herein. In certain embodiments, other fatty acids or dietary oils may also be present.

In certain embodiments, the omega-3 fatty acid ester (s) occupies about 40% (wt / wt) of the composition. In certain embodiments, the omega-3 fatty acid ester (s) occupies about 45% (wt / wt) of the composition. In certain embodiments, the omega-3 fatty acid ester (s) occupies about 50% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 55% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 60% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 65% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 70% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 75% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 80% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 85% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 90% (wt / wt) of the composition. In another embodiment, the omega-3 fatty acid ester (s) occupies about 95% (wt / wt) of the composition.

In certain embodiments, the composition is selected from the group consisting of hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosahexanoic acid, docosahexaenoic acid, A first omega-3 fatty acid ester selected from the group consisting of tetracosapentaenoic acid, tetracohexaenoic acid, or an ester thereof; And polyoxyethylene derivatives such as hexadecatrienoic acid,? -Linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosahexanoic acid, docosahexanoic acid, tetracosapentaenoic acid, A second omega-3 fatty acid ester selected from the group consisting of esters of tetracohexaenoic acid or combinations thereof; And at least one surface-active agent. The first and second omega-3 fatty acid esters selected will be different. The ratio of the first omega-3 fatty acid ester to the second omega-3 fatty acid ester should be greater than 2: 1 to 3.4: 1 (first omega-3 fatty acid ester: second omega-3 fatty acid ester). Typically, the ratio of the first omega-3 fatty acid ester to the second omega-3 fatty acid ester is about 2.4: 1. The first and second omega-3 fatty acid esters formulated comprise from about 40% to about 85% (wt / wt) of the composition. In certain embodiments, the first and second omega-3 fatty acid esters formulated comprise about 40% (wt / wt) or more of the composition. In certain embodiments, the first and second omega-3 fatty acid esters formulated comprise about 45% (wt / wt) or more of the composition. In certain embodiments, the first and second omega-3 fatty acid esters formulated comprise about 50% (wt / wt) or more of the composition. In certain embodiments, the first and second omega-3 fatty acid esters formulated comprise about 55% (wt / wt) or more of the composition. In certain embodiments, the first and second omega-3 fatty acid esters formulated comprise about 60% (wt / wt) or more of the composition. In certain embodiments, the combined first and second omega-3 fatty acid esters comprise about 65% (wt / wt) or more of the composition. In certain embodiments, the first and second omega-3 fatty acid esters formulated comprise about 70% (wt / wt) or more of the composition. In certain embodiments, the first and second omega-3 fatty acid esters formulated comprise about 75% (wt / wt) or more of the composition. In certain embodiments, the combined first and second omega-3 fatty acid esters comprise about 80% (wt / wt) or more of the composition. In certain embodiments, the first and second omega-3 fatty acid esters formulated comprise about 85% (wt / wt) or more of the composition. In certain embodiments, these mixed omega-3 fatty acid ester compositions are substantially free of other active ingredients other than omega-3 fatty acid esters. These mixed omega-3 fatty acid ester compositions may further comprise one or more terpenes and / or one or more antioxidants. Terpenes are typically substantially pure d-limonene and are present at from about 0.1% to about 5% (wt / wt) of the composition. Optionally, the composition may further comprise from about 0.1% to about 5% (wt / wt) of a natural orange oil thereof. The one or more surface active agents may be one or more of the surface active agents described herein, but are typically polysorbates and / or poloxamers, such as polysorbate 80 and pluronic F87. Surfactants are present from about 15% to about 31% (wt / wt) of the composition. Suitable antioxidant (s) for use in these mixed omega-3 fatty acid ester compositions include, but are not limited to, tocopherol and / or tocotrienol and comprise from about 0.01% to about 5% (wt / wt) Can exist. In certain such embodiments, tocopherol and / or tocotrienol may be present in an amount of from about 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6% , 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt% or 5 wt%. In certain such embodiments, the antioxidant is tocopherol present at about 0.4% by weight of the composition.

In certain embodiments, the composition comprises omega-3 fatty acid esters, for example, ethyl esters, one or more surfactants. In certain embodiments, the surfactant is selected from the group consisting of a nonionic surfactant, a cationic surfactant, an anionic surfactant, a zwitterionic surfactant, or a combination thereof. In some embodiments, the composition comprises at least one non-ionic surfactant. Nonionic surfactants generally have hydrophobic groups and reactive hydrogen atoms, such as aliphatic alcohols, acids, amides, and alkylphenols, in combination with alkylene oxides (especially ethylene oxide alone or in combination with propylene oxide). Examples of nonionic surfactant compounds include, but are not limited to, polyoxyethylene glycol sorbitan alkyl esters, block copolymers of polyethylene glycol and polypropylene glycol, ethylene glycol fatty acid esters, poly (ethylene glycol) fatty acid esters, propylene glycol fatty acid A fatty acid amide, an alkyl ester, a fatty acid amide, a fatty acid amide, a fatty acid amide, a fatty acid amide, a fatty acid amide, a fatty acid amide, a fatty acid amide, Alkyl amine oxides, lanolin and derivatives thereof, castor oil derivatives, cured castor oil derivatives, sterols and derivatives thereof, polyoxyethylene alkyl ethers, polyoxyethylene alkylallyl ethers, polyoxyethylene alkyl Amine, polyoxyethylene fatty acid amide, polyoxyethylene alkylolamide, polyoxyethylene diethanolamine fatty acid ester, polyoxyethylene trimethylol propane fatty acid ester, polyoxyethylene alkyl ether fatty acid ester, polyoxyethylene polyoxypropylene glycol, poly Oxyethylene polyoxypropylene alkyl ethers, polyoxyethylene polyoxypropylene polyhydric alcohol ethers, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, Cross-linked fatty acid esters or combinations thereof.

In certain embodiments, the surface active agent comprises a polyoxyethylene glycol sorbitan alkyl ester, a block copolymer of polyethylene glycol and polypropylene glycol, or a combination thereof.

An example of a polyoxyethylene glycol sorbitan alkyl ester is typically polysorbate. Polysorbate is a class of oily liquid derived from PEG-modified sorbitan (derivatives of sorbitol) esterified with fatty acids. A generic trade name for polysorbate includes Tween®. Twin-20, twin-60 and twin-80 are available, for example, from Akzo Nobel (Netherlands Stravinsky 2555 1077 ZZ). Exemplary polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).

An example of a block copolymer of polyethylene glycol and polypropylene glycol includes poloxamer. Poloxamers are nonionic triblock copolymers composed of hydrophobic chains at the center of polyoxypropylene (poly (propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly (ethylene oxide)). Certain poloxamers, such as those listed herein, are also known under the trade name Pluronic®, available from suppliers such as, for example, BASF AG (Ludwigshafen, Germany). Because the length of the polymer block can be tailored, there are many different poloxamers with slightly different properties. Exemplary pluronic poloxamers may also include, but are not limited to, Pluronic® 10R5, Pluronic® 17R2, Pluronic® 17R4, Pluronic® 25R2, Pluronic® 25R4, Pluronic® 31R1, Pluronic® F 108 Cast Solid Surfacta), Pluronic® F 108 NF, Pluronic® F 108 Pastille, Pluronic® F 108 Prill, Pluronic® F 108 NF Frill Poloxamer 338, Pluronic® F 127, Pluronic® F 127 Prill, Pluronic® ® F 127 NF, Pluronic® F 127 NF 500 BHT Frills, Pluronic® F 127 NF Frill Poloxamer 407, Pluronic® F 38, Pluronic® F 38 Pastel, Pluronic® F 68, Pluronic® F 68 Pastel, Pluronic® F 68 LF Passtell, Pluronic® F 68 NF, Pluronic® F 68 NF Frill Poloxamer 188, Pluronic® F 68 Prills, Pluronic® F 68 Prills, Pluronic® F 77, Pluronic® F 77 Microwave Steel, Pluronic® F 87 , Pluronic® F 87 NF, Pluronic® F 87 NF Frill Poloxamer 237, Pluronic® F 87 Frill, Pluronic® F 88, Pluronic® F 88 Passtell, Pluronic® F 88 Frill, Pluronic F 98, Pluronic® F 88 Prill, Pluronic® F 98, Pluronic® F 98 Prill, Pluronic® L 10, Pluronic® L 101, Pluronic® L 121, Pluronic® L 31, Pluronic® L 35, Pluronic® L 43 , Pluronic® L 44, Pluronic® L 61, Pluronic® L 62, Pluronic® L 62, Pluronic® L 64, Pluronic® L 81, Pluronic® L 92, Pluronic® L 44 NF INH Surfactant Pluronic® P 103, Pluronic® P 104, Pluronic® P 105, Pluronic® P 123 surfactant, Pluronic® P 65, Pluronic® P 84, Pluronic® P 85 or combinations thereof .

In certain embodiments, the composition comprises from about 15% (wt / wt) to about 31% (wt / wt) polysorbate. In certain embodiments, the polysorbate is polysorbate 80. In another embodiment, the composition comprises from about 0.5% (wt / wt) to about 5% (wt / wt) of poloxamer. In certain embodiments, the polysorbate is polysorbate 20, polysorbate 60, polysorbate 80, or a combination thereof, and the poloxamer is selected from the group consisting of Pluronic F 87, Pluronic L61, Pluronic F 127, to be. In some embodiments, the composition comprises about 50% (wt / wt) to about 80% (wt / wt) omega-3 fatty acid esters, such as ethyl esters; From about 15% (wt / wt) to about 99% (wt / wt) polysorbate; And from about 0.05% (wt / wt) to about 50% (wt / wt) of poloxamer. In certain embodiments, the one or more surface active agents comprise about 15% (wt / wt) to about 31% (wt / wt) polysorbate, such as polysorbate 80 and about 0.5% / wt) to about 5% (wt / wt) of a poloxamer such as Pluronic F87.

In certain embodiments, the polysorbate comprises from about 15% (wt / wt) to about 70% (wt / wt) of the composition. In certain embodiments, the polysorbate comprises from about 15% (wt / wt) to about 50% (wt / wt) of the composition. In certain embodiments, the polysorbate comprises from about 15% (wt / wt) to about 31% (wt / wt) of the composition. In certain embodiments, the polysorbate comprises from about 15% (wt / wt) to about 25% (wt / wt) of the composition. In certain embodiments, the polysorbate comprises from about 15% (wt / wt) to about 20% (wt / wt) of the composition. In certain embodiments, the polysorbate comprises from about 20% (wt / wt) to about 31% (wt / wt) of the composition.

In certain embodiments, the poloxamer comprises from about 0.5% (wt / wt) to about 5% (wt / wt) of the composition. In certain embodiments, the poloxamer occupies from about 0.5% (wt / wt) to about 4% (wt / wt) of the composition. In certain embodiments, the poloxamer comprises from about 0.5% (wt / wt) to about 3% (wt / wt) of the composition. In certain embodiments, the poloxamer comprises from about 0.5% (wt / wt) to about 2% (wt / wt) of the composition. In certain embodiments, the poloxamer comprises from about 0.5% (wt / wt) to about 1% (wt / wt) of the composition.

In some embodiments, the composition comprises at least one anionic surfactant. Exemplary "anionic surfactants" include, but are not limited to, N-acyl-L-glutamic acid diethanolamine, N-acyl-L-glutamic acid triethanolamine, sodium N-acyl-L- glutamate, sodium alkanesulfonate, (C11, C13, C15) sulfuric acid triethanolamine, alkyl (C12 to C14) sulfuric acid triethanolamine, liquid alkylsulfuric acid triethanolamine , Sodium alkyl (C12, C13) sulfate, liquid sodium alkyl sulfate, sodium isoethionate, sodium lacto-isostearate, disodium undecylenoyl amidoethyl sulfosuccinate, triethanolamine sulfooleate, sodium sulfooleate Octyl oleate, sodium oleamide sulphosuccinate, potassium oleate, sodium oleate, morpholine oleate, oleoyl sarcosine, oleoylmethyltaurine sodium salt, Potassium soap, carboxylated polyoxyethylene tridodecyl ether, sodium salt of carboxylated polyoxyethylene tridodecyl ether (3-ethyl oxide "EO"), sodium salt of carboxylated polyoxyethylene tridecyl ether, , Triethanolamine N-cured tallow fatty acid-acyl-L-glutamate, sodium N-cured tallow fatty acid-acyl-L-glutamate, sodium cured coconut fatty acid glyceryl sulfate, sodium diundecylenoyl amidoethyl sulfosuccinate Sodium stearoyl-L-glutamate, stearoylmethyltaurine sodium salt, sodium stearoyl-L-glutamate, potassium stearate, triethanolamine stearate, sodium stearate, sodium N-stearoyl- Dioctyl sulfosuccinate, liquid sodium dioctyl sulfosuccinate, liquid disodium polyoxyethylene monooleylamidosulfosuccinate (2 EO), disodium polyoxyethylene lauroylethanolamide sulfosuccinate (5 EO), disodium lauryl sulfosuccinate, diethanolamide cetyl sulfate, sodium cetyl sulfate, base for soap, sodium cetyl (30%), ammonium polyoxyethylene alkyl ether sulfate (3 EO), liquid phase di (3-ethylhexyl) phosphate, triethanolamine tridecyl sulfate, potassium palmitate, sodium palmitate, palmitoylmethyltaurine sodium salt, liquid castor oil fatty acid sodium salt Ethanol amine polyoxyethylene alkyl (C12, C13) ether sulfate, liquid triethanolamine polyoxyethylene alkyl ether sulfate (3 EO), triethanolamine polyoxyethylene alkyl (C11, C13, C15) ether sulfate (1 EO), triethanolamine Polyoxyethylene alkyl (C12, C13) ether sulfate (3 EO), liquid sodium polyoxyethylene alkyl ether sulfone (3 EO), sodium polyoxyethylene alkyl (C11, C13, C15) ether sulfate (1 EO), sodium polyoxyethylene alkyl (C11 to C15) ether sulfate (3 EO), sodium polyoxyethylene alkyl (3 EO), sodium polyoxyethylene alkyl (C12 to C14) ether sulfate (3 EO), sodium polyoxyethylene alkyl (C12 to C15) ether sulfate (3 EO), disodium polyoxyethylene alkyl C12 to C14) sulfosuccinate (7 EO), sodium polyoxyethylene undecyl ether sulfate, liquid sodium polyoxyethylene octyl phenyl ether sulfate, ammonium polyoxyethylene oleyl ether sulfate, disodium polyoxyethylene lauryl sulfosuccinate Sodium polyoxyethylene nonylphenyl ether sulfate, sodium polyoxyethylene pentadecyl ether sulfate, triethanol amine polyoxy Sodium polyoxyethylene myristyl ether sulfate (3 EO), liquid sodium polyoxyethylene lauryl ether acetate (16 EO), ammonium polyoxyethylene lauryl ether sulfate (2 EO), triethanolamine polyoxyethylene lauryl ether sulfate, sodium polyoxyethylene lauryl ether sulfate, diethanolamine myristyl sulfate, sodium myristyl sulfate, potassium myristyl sulfate, sodium N-myristoyl-L- Glutamate, sodium myristoyl methylaminoacetate, liquid myristoylmethyl-alanine sodium salt, myristoylmethyltaurin sodium salt, medical soap, triethanolamine / magnesium cocoalkyl sulfate, triethanolamine N- coconut oil fatty acid -L-glutamate, sodium N-coco Nut Oil Fatty Acyl L-Glutamate, Sodium Coconut Oil Fatty Acid Ethyl Sulfonate, Coconut Oil Fatty Acid Potassium Salt, Liquid Coconut Oil Fatty Acid Potassium Salt, Sodium N-Coconut Oil Fat / Cured Fat-Acyl-L- Glutamate, Coconut Oil fatty acid sarcosine, coconut oil fatty acid sarcosine triethanolamine salt, coconut oil fatty acid sarcosine sodium salt, coconut oil fatty acid triethanol amine salt, coconut oil liquid triethanolamine salt of fatty acid, coconut oil fatty acid sodium salt, coconut oil fatty acid methyl alanine sodium Salt, liquid coconut oil fatty acid methyl alanine sodium salt, coconut oil fatty acid methyl taurine potassium salt, coconut oil fatty acid methyl taurine sodium salt, sodium laurylaminodipropionate, liquid sodium laurylaminodipropionate (30%), Sodium lauryl sulfoxide Three Tate; Sodium lauryl sulfate, sodium lauryl benzenesulfonate, lauryl sulfate, ammonium lauryl sulfate, potassium lauryl sulfate, diethanolamine lauryl sulfate, triethanolamine lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, monoethanolamine lauryl sulfate , Sodium laurate, triethanolamine laurate / myristate, triethanolamine lauroyl-L-glutamate, sodium N-lauroyl-L, sodium laurylate, triethanolamine laurylate, triethanolamine laurate, Sodium lauryl sulfate, lauryl sarcosine, sodium lauroyl sarcosine triethanolamine salt, lauroyl sarcosine sodium, sodium lauroylmethyl-beta -alanine sodium salt, lauroylmethyltaurine Sodium salt, liquid lauroylmethyltaurine sodium salt or a combination thereof.

In certain embodiments, the anionic surfactant (s) comprises from about 0.05% (wt / wt) to about 25% (wt / wt) of the composition. In certain embodiments, the anionic surfactant (s) comprises from about 0.05% (wt / wt) to about 15% (wt / wt) of the composition. In certain embodiments, the anionic surfactant (s) comprises from about 0.05% (wt / wt) to about 5% (wt / wt) of the composition. In certain embodiments, the anionic surfactant (s) comprises from about 0.5% (wt / wt) to about 3% (wt / wt) of the composition. In certain embodiments, the anionic surfactant (s) occupies about 0.7% (wt / wt) of the composition. In certain embodiments, the anionic surfactant (s) comprises sodium lauryl sulfate.

In certain embodiments, the composition comprises omega-3 fatty acid esters, such as ethyl esters, and further comprises one or more surfactants. In certain embodiments, the surface active agent is selected from the group consisting of a combination of polysorbate or polysorbate and a combination of anionic surfactant or anionic surfactant, or a combination of polysorbate and anionic surfactant. In another embodiment, the composition comprises from about 15% (wt / wt) to about 31% (wt / wt) polysorbate. In certain embodiments, the polysorbate is polysorbate 80. In another embodiment, the composition comprises from about 0.5% (wt / wt) to about 5% (wt / wt) of the anionic surfactant (s). In certain embodiments, the polysorbate is polysorbate 80, polysorbate 20 or a combination thereof, and the anionic surfactant is sodium lauryl sulfate. In some embodiments, the composition comprises from about 40% (wt / wt) to about 85% (wt / wt) omega-3 fatty acid esters, such as ethyl esters; And about 15% (wt / wt) to about 99% (wt / wt) polysorbate; And from about 0.05% (wt / wt) to about 50% (wt / wt) of the anionic surfactant (s). In some embodiments, the composition comprises about 50% (wt / wt) to about 80% (wt / wt) (90) omega-3 fatty acid esters, such as ethyl esters; And about 15% (wt / wt) to about 99% (wt / wt) polysorbate; And from about 0.05% (wt / wt) to about 2% (wt / wt) of anionic surfactant (s), for example, sodium lauryl sulfate. In some embodiments, the composition comprises about 0.7% (wt / wt) sodium lauryl sulfate.

In certain embodiments, the poloxamer comprises from about 0.05% (wt / wt) to about 25% (wt / wt) of the composition. In certain embodiments, the poloxamer comprises from about 0.05% (wt / wt) to about 15% (wt / wt) of the composition. In certain embodiments, the poloxamer comprises from about 0.05% (wt / wt) to about 5% (wt / wt) of the composition. In certain embodiments, the poloxamer comprises from about 0.5% (wt / wt) to about 3% (wt / wt) of the composition.

In some embodiments, the composition comprises additional surface active agents such as zwitterionic and cationic surfactants. Examples of such surface active agents include, but are not limited to, bile acids (e.g., cholic acid, chenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurokenodoxycholic acid, tauriolic acid, For example, sodium, potassium, lithium), natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrox, cholesterol, cholesterol, Cholesterol, wax and lecithin), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, Polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxybis (propyleneglycol monostearate, Polymers such as carrageenan, cellulose derivatives such as carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyoxyethylene esters such as polyoxyethylene monostearate (Myrj 45), polyoxyethylene hardened castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters Oxyethylene ethers such as polyoxyethylene lauryl ether (Brij 30), poly (vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate Octyl, oleic acid, ethyl laurate, sodium lauryl sulfate, setrumonium bromide, cetylpyridine Sodium chloride, benzalkonium chloride, sodium docusate or combinations thereof.

Compositions suitable for self-micellization as described herein generally have an HLB of from about 12 to about 18. In certain embodiments, the composition has an HLB of about 12.0 to about 14.0. In certain embodiments, the composition has an HLB of about 13.0 to about 14.0. In certain embodiments, the composition has an HLB of about 13.5 to about 13.8. The total HLB of all surfactants or surfactants used in the composition is generally from about 12 to about 18. In some embodiments, the total HLB of all surfactants used in the composition is generally from about 12 to about 15. In some embodiments, the total HLB of all surfactants or surfactants used in the composition is generally from about 13 to about 15.

In certain embodiments, the at least one surfactant or surfactant has an HLB of at least 8.0. In some embodiments, the surfactant (s) or surfactant (s) have a combined HLB in the range of about 13 to about 15. Only about 25% (wt / wt) to about 42% (wt%) of HLB 17 is needed, since it is necessary to reduce the amount of surfactant or surfactant as the HLB value of the surfactant (s) / wt) surfactant (s) or surfactant (s) may be required.

In certain embodiments, the composition further comprises terpenes. In certain embodiments, the terpene is d-limonene. In one embodiment, the terpene is cyclic terpene. In one embodiment, terpene is d-limonene ((+) - limonene) which is the (R) -enantiomer. In one embodiment, terpenes are L-limonene, which is an (S) -enantiomer. In one embodiment, terpenes are racemic limonene, also known as dipentene. In another embodiment, the terpene is terpenoid. In another embodiment, the terpenes or terpenes are derived from natural oils such as citrus oils such as orange oil. Other terpenes such as monoterpenes having a structure similar to d-limonene (e.g., terpinene, terpinolene, phellandrene or menthol) are contemplated. In certain embodiments, the composition further comprises substantially pure d-limonene which comprises from about 0.1% to about 5% by weight of the composition. In certain other embodiments, the composition further comprises a natural orange oil which comprises from about 0.1% to about 5% by weight of the composition. d-limonene or orange oil may help to eliminate and / or minimize side effects from oral administration of omega-3 fatty acid esters. These side effects include reflux, frequent trimming, GERD, hypertrophy, increased intestinal gas, fishy taste, acute respiration, fishy smell, nausea, diarrhea, or a combination thereof.

In another embodiment, the composition further comprises an antioxidant. In certain embodiments, the antioxidant is selected from the group consisting of one or more tocopherols, one or more tocotrienols, or combinations thereof. In another embodiment, the compositions described herein may comprise one or more tocopherol (s). In an embodiment that additionally comprises one or more antioxidant (s), the antioxidant (s) may be present from about 0.01% to about 5% by weight of the composition. In such embodiments, the antioxidant (s) may be present in an amount of from about 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6% And may be present in an amount of 0.8 wt%, 0.9 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt% or 5 wt%. In certain embodiments, the antioxidant (s) may be present at about 0.4% by weight of the composition.

In one or more additional embodiments there is provided a composition comprising a micelle formed by adding an aqueous medium to the composition prior to administration of a composition of any of the embodiments provided herein to a subject in need of treatment . Alternatively, the micelle may also be formed when the composition is added to the aqueous medium. In certain embodiments, the micelle has a diameter of about 10 [mu] m or less. In another embodiment, substantially all of the micelles have an average diameter of about 1 [mu] m to about 10 [mu] m. In certain embodiments, the micelle has an average diameter of about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 μm. In certain embodiments, the micelle is stable at room temperature. In certain embodiments, the composition forms micelles in an aqueous medium at an acidic pH. In certain other embodiments, the composition forms micelles in 0.1 N HCl.

In yet another embodiment, one or more (5Z, 8Z, 11Z, 14Z, 17Z) -Ecosa-5,8,11,14,17-pentenoic acid (EPA) , 16Z, 19Z) -docosa-4,7,10,13,16,19-hexaenoic acid (DHA) ester, wherein the ratio of EPA ester to DHA ester of greater than 2.0: Wherein the concentration of the EPA ester, DHA ester, or combination thereof comprises from about 40% to about 85% by weight of the total amount of omega-3 ester in the composition. In certain embodiments, the ratio of EPA ester to DHA ester is from about 2.0: 1.0 to about 2.5: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.1: 1.0 to about 2.4: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.1: 1.0 to about 2.3: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.1: 1.0 to about 2.2: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is 2.4: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.0: 1.0 to about 3.3: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.2: 1.0 to about 3.2: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.4: 1.0 to about 3.1: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.5: 1.0 to about 3.0: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.6: 1.0 to about 2.9: 1.0. In another embodiment, the ratio of EPA ester to DHA ester is from about 2.7: 1.0 to about 2.8: 1.0. In certain embodiments, the ratio of EPA ester to DHA ester in the composition is greater than 2.0: 1.0.

In certain embodiments, the omega-3 fatty acid esters used herein are substantially pure. In certain embodiments, the omega-3 fatty acid ester is from about 80% to about 99% pure. In certain embodiments, omega-3 fatty acid esters are at least 80%, 85%, 90%, 92%, 94%, 96%, 98% or 99% pure.

How to treat cardiovascular conditions or disorders

Comprising administering to a subject in need of treatment a cardiovascular condition or disorder a therapeutically effective amount of a composition of any of the embodiments of the presently provided embodiments or of any of the embodiments provided herein, A method of treating one or more cardiovascular conditions or disorders in a subject is provided.

Accordingly, in certain embodiments, the cardiovascular condition or disorder is selected from the group consisting of hypertension, hyperlipidemia, hypertriglyceridemia, atherosclerosis, transient ischemic attack, systolic dysfunction, diabetic dysfunction, aneurysm, aortic dissection, (AMI), acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), angina pectoris, unstable angina pectoris (UA), stable angina pectoris (SA) Cardiovascular and systemic conditions including congestive heart failure, dilated congestive cardiomyopathy, hypercardiomyopathy, restrictive cardiomyopathy, pulmonary heart disease, arrhythmia, valvular heart disease, endocarditis, pulmonary embolism, venous thrombosis, peripheral vascular disease and peripheral arterial disease Or disorder.

In certain embodiments, the cardiovascular condition or disorder is hypertension, hyperlipidemia, or a combination thereof. In another embodiment, the cardiovascular condition or disorder is hypertriglyceridemia.

In another embodiment, there is provided a method of treating hypertriglyceridemia comprising administering to a subject a composition having a fasting baseline TG level of from about 200 mg / dL to about 500 mg / dL, There is provided a method of treating moderate to severe hyperglycemia in a subject in need thereof. In one embodiment, the composition comprises from about 0.5 g to about 1 g, from about 1 g to about 2 g, from about 2 g to about 4 g, from about 4 g to about 6 g, or from about 6 g to about 10 g &Lt; / RTI &gt;

In certain embodiments, the total amount of fasted TG in the subject's serum is reduced by 20% or more within 30 days of administration of the composition or micelle in a subject having a fasted serum TG of at least 150 mg / dL at the beginning of the dosage regimen. In another embodiment, the total concentration of low density lipoprotein (LDL) in the subject serum is not substantially increased within 30 days of administration of the composition or micelle. In certain embodiments, the therapeutically effective amount of the composition or micelle comprises at least 0.5 g / day omega-3 fatty acid esters. In another embodiment, subject serum has a concentration of at least 20 nmol / mL of combined EPA, DHA, or a combination thereof within 4 hours of administration of the composition or micelle.

In a further embodiment, a method is provided wherein the ratio of high density lipoprotein is increased relative to LDL in the subject's serum by administering to the subject a composition comprising at least one omega-3 fatty acid ester. In certain embodiments, the administration is oral. In certain embodiments, the subject is a human.

Some embodiments include methods wherein one or more omega-3 fatty acid esters self-micelle upon contact with an aqueous medium and one or more omega-3 fatty acid esters are absorbed by the subject at a rate substantially independent of the food effect upon oral administration, A composition comprising at least one omega-3 fatty acid ester and at least one surfactant is administered to a subject. In certain embodiments, a reduction in food effect can reduce F by 30% or more, 40% or more, 50% or more, or 75% or more.

Wherein one or more omega-3 fatty acid esters are self-micellized upon contact with the aqueous medium and one or more of the omega-3 fatty acid esters is orally administered to the subject by at least one omega-3 fatty acid ester that is absorbed by the subject at a rate substantially independent of the food effect There is provided a method of administering to a subject a composition comprising a fatty acid ester and at least one surfactant. In certain embodiments, the composition is a composition of any of the embodiments provided herein. In another embodiment, at least 0.5 g / day of omega-3 fatty acid ester is administered to the subject.

In another embodiment, the composition described herein is administered to a subject in need thereof, for example, from about 1 to about 200 weeks, from about 1 to about 100 weeks, from about 1 to about 80 weeks, from about 1 to about 50 weeks, Week, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks, Lt; / RTI &gt; In another embodiment, the compositions described herein are administered to a subject in need of treatment over an extended period of time, for a limited period of time.

In another embodiment, the subject's serum has at least 20 nmol / mL concentration of one or more omega-3 fatty acid esters within 4 hours of administration of the composition. In another embodiment, the subject's serum has at least 50 nmol / mL concentration of one or more omega-3 fatty acid esters within 4 hours of administration of the composition. In another embodiment, the subject's serum has at least 100 nmol / mL concentration of one or more omega-3 fatty acid esters within 4 hours of administration of the composition. In another embodiment, the concentration of one or more omega-3 fatty acid esters in the subject's serum may be increased upon increasing the dosage of the composition.

In certain embodiments, a method of treating a subject in need of treatment, comprising administering a composition of any of the embodiments provided herein or of any of the embodiments provided herein, There is provided a method for minimizing / minimizing and eliminating adverse effects from oral administration of omega-3 fatty acid esters in the presence of a pharmaceutically acceptable carrier. In certain embodiments, the occurrence of side effects is eliminated in a manner that minimizes side effects. In some embodiments, non-limiting examples of adverse effects include, but are not limited to, reflux, frequent trimming, GERD, hyperlipidemia, increased intestinal gas, fishy taste, acute respiration, fishy smell, nausea, diarrhea, .

In certain embodiments, a subject in need of treatment, comprising administering a composition of any of the embodiments provided herein or of any of the embodiments provided herein, is administered one or more terpenes A method of minimizing / minimizing and eliminating adverse effects from oral administration of omega-3 fatty acid esters in the presence of natural or natural orange oil is provided. In certain embodiments, the one or more terpenes are typically d-limonene of greater than 95% purity, but this is not necessarily the case. In certain embodiments, the occurrence of side effects is eliminated in a manner that minimizes side effects. In some embodiments, non-limiting examples of adverse effects include, but are not limited to, reflux, frequent trimming, GERD, hyperlipidemia, increased intestinal gas, fishy taste, acute respiration, fishy smell, nausea, diarrhea, .

Some embodiments provide a method of reducing food effect in a subject in need of treatment, comprising administering to a human subject a therapeutically effective amount of any of the compositions described herein. In certain embodiments, the food effect is substantially eliminated.

There is also provided a method of improving patient compliance during oral administration of an omega-3 fatty acid ester to a subject in need of treatment comprising administering a composition as described herein.

The composition described herein is a non-omega-3 fatty acid ester lipid-lowering or cholesterol lowering agent selected from the group consisting of a cholesterol absorption inhibitor, a bile acid sequestrant / resin, a statin, a niacin and a derivative, an MTP inhibitor, a fibrate and a CETP inhibitor May be administered to a subject in need of such administration. These lipid-lowering agents or cholesterol lowering agents can be classified by a mechanism of action. For example, cholesterol absorption inhibitors inhibit dietary cholesterol absorption and inhibit the reabsorption of bile cholesterol. Examples of cholesterol absorption inhibitors include, but are not limited to, phytosterols, ezetimibe, and (3R, 4S) -1,4-bis (4-methoxyphenyl) -3- Dinon (SCH 48461). The bile acid sequestrant / resin is a polymeric compound and functions as an ion exchange resin. The bile acid sequestrants replace bile acids with anions such as chloride ions. By doing so, they bind to bile acids and block long-term circulation of bile acids. Since the bile acid sequestrant is a large polymeric structure, it is not well absorbed from the digestive tract into the bloodstream. Thus, the bile acid sequestrants, along with any bile acid bound to the drug, are passed through the gastrointestinal tract and excreted into the feces. Examples of bile acid sequestrants / resins include, but are not limited to, cholestyramine, cholinesterb and cholestipol. Statins are a class of compounds that inhibit the enzyme HMG-CoA reductase. Examples of statins include, but are not limited to, rosuvastatin, lovastatin, fluvastatin, simvastatin, pravastatin and atorvastatin. Niacin and its derivatives are believed to function by stimulating the G-protein coupled receptor GPR109A, which induces lipolysis inhibition in adipose tissue. Examples of niacin and derivatives thereof include, but are not limited to, niacitol, niacin, nicofuranose, aluminum nicotinate, nicotinyl alcohol and acipimox. MTP (microsomal triglyceride transfer protein) is a lipid transfer protein necessary for the assembly and secretion of ultra-low density lipoprotein by the liver and for the assembly and secretion of the kilo-micron by the intestine. Thus, inhibitors of MTP reduce levels of plasma LDL-C. Examples of MTP inhibitors include, but are not limited to, romitafide for use in humans and dirrotapide and mitraparate for use in dogs. Rodent and human studies suggest that fibrates exert their hypolipidemic effects through several mechanisms. Examples of fibrates include, but are not limited to, benazepibrate, cyprofibrate, clofibrate, gemfibrozil and fenofibrate. CEPT (cholesteryl ester transfer protein) inhibitors improve the plasma lipid profile by increasing HDL ("good" cholesterol containing particles) and decreasing LDL ("bad" cholesterol containing particles). Examples of CETP inhibitors include, but are not limited to, anacetrapib and eva setaplav.

In addition to the disease conditions described above, several other conditions or disorders can also benefit from treatment with the compositions described herein, for example, the following conditions or disorders: metabolic syndrome; Macular degeneration [AREDS2 Research Group et. al. The Age-Related Eye Disease 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1), Opthalmology. 2012 Nov. 119 (11): 2282-9. doi 10.1016 / j.optha 2012.05.027. Epub 2012 Jul 26; SanGiovanni JP et al., Ω-3 long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: A prospective cohort study from the Age-Related Eye Disease Study . Am. J. Clin. Nutr. 2009; 90: 1601-70.]; Cognitive impairment resulting from surgery or, for example, from traumatic brain injury resulting from concussion [Lewis M. et. al. Therapeutic use of omega-3 fatty acids in severe head trauma. Am J Emerg Med. 2013 Jan; 31 (1): 273. doi: 10.1016 / j. Epub 2012 Aug 3; Mills JD. et. al. Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid in traumatic brain injury. Neurosurgery. 2011 Feb; 68 (2): 474-81; discussion 481. doi: 10.1227 / NEU.0b013e3181ff692b.]; Major depression, suicide, and postpartum depression [Logan AC. Omega-3 fatty acids and major depression: a primer for the mental health professional. Lipids Health Dis . 2004 Nov 9; 3:25; Lewis MD et al. Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison. J Clin Psychiatry . Dec 2011 72 (12): 1585-90. doi: 10.4088 / JCP.11m06879. Epub 2011 Aug 23; Makrides M. et. al. Docosahexaenoic acid and post-partum depression - is there a link? Asia Pac J Clin Nutr. 2003; 12 Suppl: S37.]; Inflammation [Kelley DS et. al. DHA supplementation decreased serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men. J Nutr. 2009 Mar; 139 (3): 495-501. doi: 10.3945 / jn.108.100354. Epub 2009 Jan 21]; Primary sclerosing cholangitis [Martin CR. et. al. The safety and efficacy of oral docosahexaenoic acid supplementation for the treatment of primary sclerosing cholangitis - a pilot study. Aliment Pharmacol Ther. 2012 Jan; 35 (2): 255-65. doi: 10.1111 / j.1365-2036.2011.04926.x. Epub 2011 Nov 30.], Women's borderline personality disorder [Zanarini MC et al. Omega-3 Fatty acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003 Jan; 160 (1): 167-9.], Breast cancer [Bougnoux P. et al. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer . Dec 15, 101 (12): 1978-85. doi: 10.1038 / sj.bjc.6605441. Epub 2009 Nov 17.], non-alcoholic fatty liver disease [Parker HM. et. al. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012 Apr; 56 (4): 944-51. doi: 10.1016 / j.jp.2011.08.018. Epub 2011 Oct 21; Nobili V. Docosahexaenoic acid for the treatment of fatty liver: Randomized controlled trial in children. Nutr Metab Cardiovasc Dis. 2012 Dec 7 pii: S0939-4753 (12) 00256-6. doi: 10.1016 / j.numecd.2012.10.010. [Epub ahead of print]; Christopher MD et. al. Menhaden oil reduced high-fat diet-induced markers of hepatic damage, steatosis, inflammation, and fibrosis in obese Ldlr - / - mice. J Nutr. 2012 Aug; 142 (8): 1495-503. doi: 10.3945 / jn.112.158865. Epub 2012 Jun 27.], and improvement in cognition and behavior in children [Richardson AJ. et. al. Docosahexaenoic acid for reading, cognition and behavior in children aged 7-9 years: a randomized, controlled trial (the DOLAB Study). PLoS One. 2012; 7 (9): e43909. doi: 10.1371 / journal.pone.0043909. Epub 2012 Sep 6]. These conditions or disorders can be treated by administering the compositions described herein to a subject, typically a human, in need of such administration.

Kit

Packaged pharmaceutical kits are included herein. The kit includes instructions for using the dosage form to treat a subject having a disease or disorder responsive to treatment by administering the composition described herein in unit dosage form and administering a dosage form comprising the composition as described herein .

A packaged pharmaceutical kit may provide prescription information, prescription-free medical usage information, and / or nutritional information for a dosage form, including, for example, for a subject or a healthcare provider, without limitation, as a mark in a packaged pharmaceutical kit do. The information contained in the kit may include, for example, but is not limited to, the efficacy, dose and administration, contraindications, and side effects associated with the omega-3 fatty acid dosage form. The dosage and administration information may include, for example, the number of administrations as well as administration of the composition with or without food.

In certain embodiments, dosage forms comprising the compositions provided herein are in the form of liquid water or capsules provided as blister packs or bottles with prescription medical usage information and / or nutritional information.

A packaged pharmaceutical kit may comprise one or more of the compositions described herein as the sole active ingredient. In other embodiments, one or more of the compositions described herein may contain one or more other active agents other than non-omega-3 esters, such as, but not limited to, cholesterol absorption inhibitors, bile acid sequestrants / Derivative, an MTP inhibitor, a fibrate, and a CETP inhibitor.

Dosage form

Any of the compositions provided herein comprising one or more omega-3 fatty acid esters may be provided as a pharmaceutical composition, a pharmaceutical formulation or a dietary supplement.

The pharmaceutical compositions described herein may further comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, carriers, preservatives and / or colorants. General considerations in the compositions and preparation of pharmaceutical compositions can be found, for example, in Remington's Science and Practice of Pharmacy 21st ed., Lippincott Williams &amp; Wilkins, 2005.

In certain embodiments, the compositions described herein may be formulated as a liquid for oral administration. Liquid compositions include solutions, suspensions and emulsions. Examples of liquid pharmaceutical preparations include solutions containing propylene glycol solutions and sweeteners for oral solutions, suspensions and emulsions. When the liquid composition is contacted with an aqueous medium, e. G., An aqueous medium having an acidic environment, the composition forms micelles.

In certain embodiments, the dosage form comprises micelles previously formed prior to administration to a subject in need of such administration. These preformed micelles are stable at room temperature.

In another embodiment, the compositions described herein may be formulated as a filler material for soft gelatine capsules. Likewise, when the contents of the soft gelatine capsules are contacted with an aqueous medium, the composition upon formation of the capsule disintegrates to micelles.

Capsules can be made, for example, by placing the composition described above inside a capsule shell. Capsules are dosage forms that are administered with a particular container or enclosure containing an active agent. In some embodiments, the compositions described herein can be filled with a soft capsule. Capsule shells may be made from methyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, or modified gelatin or starch or other materials. Hard shell capsules are typically made from a blend of relatively high gel strength bone and porcine gelatin gels. In some embodiments, the unit dosage form is a gel capsule. In some embodiments, the capsule shell is a glycerine capsule shell, e.g., product number GSU0051 manufactured by SwissCaps and satisfying the USP 25 condition (SwissCaps, USA 14193 SW 119th Ave., Miami / Fla. US 33186). In another embodiment, the capsule is a bovine gelatin shell, e.g., Swiss Caps product number GSU0708. Other suitable capsule shell materials include polyethylene, polypropylene, poly (methyl methacrylate), polyvinyl chloride, polystyrene, polyurethane, polytetrafluoroethylene, nylon, polyformaldehyde, polyester, cellulose acetate and nitrocellulose do. The capsule shell itself may contain minor amounts of dyes, opacifiers, plasticizers and preservatives. In addition, conventional methods for preparing other solid dosage forms, such as capsules, suppositories, etc., are well known. The gelatin capsule shell can also be made from tapioca, grass, vegetable-derived or fish-derived gelatin. For example, K-CAPS (Capsuline, Inc. Pompano Beach, Fla.) Is a Kosher soft capsule shell of certified vegetable origin. Other vegetable derived gelatin capsules can be made with vegetable derived hydroxypropylmethylcellulose (HPMC). The capsule shell may also comprise modified corn starch, glycerol and carrageenan as a gelling agent.

In another embodiment, the capsule is filled with the composition described herein with a shell comprising a material of a rate-limiting membrane including a coating material. The capsule shell may be made of a porous or pH-sensitive polymer which is produced by a thermoforming process. In certain embodiments, the capsule shell is in the form of an asymmetric membrane: a membrane that has a thin skin on one side and is composed of a porous material that is highly permeable to most thickness.

Another useful capsule, "inflatable plug device" can be used. The composition described herein can be inserted into a non-dissolving capsule-half of a device where one end is sealed with a hydrogel plug. Such a hydrogel plug expands in an aqueous environment, expands for a predetermined period of time, and exits the capsule, leaving the active agent in the capsule and opening a port that can be delivered to the aqueous environment. Preferred hydrogel-plug capsules are prepared by dissolving the active agent from the dosage form until the dosage form has exited the stomach and remains in the small intestine for at least about 15 minutes, preferably about 30 minutes, until the minimum amount of omega-3 fatty acid ester is released from the stomach or small intestine Substantially not. This type of hydrogel-plug capsule is described in patent application WO 90/19168.

The dosage form may especially include a plasticizer in the capsule shell. Suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, triethylcellulose, triacetin, glycerin, Sorbitol, sorbitan, or combinations thereof.

In a further embodiment, the composition may be formulated as a liquid for parenteral administration.

The composition may be formulated into one or more dosage units. In some embodiments, it may be advantageous to formulate the oral compositions in dosage unit form for ease of administration and uniformity of dosage. The dosage unit form described in some embodiments may refer to a physically separated unit suitable as a unit dose for a subject to be treated; Each unit comprises a predetermined amount of the active composition calculated to have the desired therapeutic effect in association with a suitable pharmaceutical carrier. In certain embodiments, the dosage form may optionally comprise a flavoring agent, such as an orange oil, a substantially pure d-limonene, and a combination of antioxidants such as tocopherol, ascorbyl palmitate or an antioxidant .

Functional food

In certain embodiments, the compositions provided herein comprise pre-formed micelles prior to administration to a subject in need of such administration. These pre-formed micelles are stable at room temperature.

Thus, the pre-formed micelles or pre-micellised compositions described herein can be added to the food product as part of a healthy diet to enhance the subject's omega-3 fatty acid level, Lt; RTI ID = 0.0 &gt; oral / parenteral &lt; / RTI &gt;

In certain embodiments, the functional food may be a food or drinkable composition, such as a food, such as a chewable or edible bar, a candy confectionery product (such as a chocolate bar), a cookie, a juice drink, Baking goods (eg brownies), biscuits, lozenges or chewing gums. Examples of chewable or edible bars include chocolate bars or energy bars. Such functional foods may be particularly useful to persons participating in sports or other forms of exercise.

In certain embodiments, the functional food may also be in the form of, for example, butter, margarine, bread, cake, milk shake, ice cream, yogurt and other fermented milk products.

In certain embodiments, the functional food may also be in the form of a liquid that is sprayed onto meat, salad, or other food.

Other forms of functional food may be breakfast cereals, for example, cereal flakes, muesli, bran, oatmeal.

When the functional food product is in a drinkable form, the composition described herein may be added directly to a drink, for example, plain milk, flavored milk, fermented milk product or juice. The composition will form micelles comprising omega-3 fatty acid esters in a drinkable product.

Where the functional food is in the form of a solid edible product, the composition described herein may first be added to the aqueous medium and the composition will form micelles as described herein. The aqueous medium containing micelles can then be sprayed onto the solid edible product or mixed with the ingredients in the manufacture of edible products.

The invention is further defined with reference to the following examples, which are not intended to limit the scope of the invention. It will be apparent to those skilled in the art that many modifications may be made to the materials and methods without departing from the spirit and scope of the invention.

Non-limiting examples

Example 1

The amounts and ratios (%) of the components occupying the composition are shown in Table 1:

Composition (filler) / dosage form ingredient Amount (mg) % (wt / wt) Total omega-3 fatty acid ethyl ester 754.3 68.57 - EPA ethyl ester 392.2 35.65 - DHA ethyl ester 165.9 15.08 Polysorbate 80 337.9 30.72 Pluronic F87 7.8 0.71 Gelmat / dosage form ingredient Amount (gm) % (wt / wt) gelatin 270 40 glycerin 135 20 Purified water 270 40

The preparation of a dosage form comprising a composition of one embodiment comprises the steps of: a) preparing the composition (filling mass), b) preparing the gel mass used to encapsulate the filling mass, and c) encapsulating . Steps (a) and (b) may be performed in any order.

The process of preparing the composition is initiated by weighing appropriate amounts of polysorbate 80 and pluronic F87 according to the desired batch size and mixing them homogeneously at 60 DEG C in a stainless steel tank. After cooling the mixture to room temperature, the substantially pure omega-3 fatty acid ethyl ester mixture is transferred quantitatively under vacuum to the same stainless steel tank containing Polysorbate 80 and Pluronic F87. This mixture is mixed homogeneously at room temperature again before blanketing with nitrogen. This final composition is also referred to as "filler mass ".

The gelmat process is initiated by weighing an appropriate amount of glycerin and an appropriate amount of water according to the desired batch size and mixing them homogeneously in a separate stainless steel mixer at about 80 占 폚. Then, an appropriate amount of gelatin is weighed according to the batch size, added to the glycerin / water mixture, and homogenized again at 80 DEG C before degassing under vacuum. These final blends, including glycerin / water / gelatin, are referred to as "gel mass ".

Depending on the desired shape of the capsule, suitable dies and delivery tubing may be installed in a soft gel encapsulation machine (SS-60 Softgel Encapsulation Machine, SKY Softgel Co. Ltd., Incheon, Korea) The filling mass is pumped into a die containing a pre-formed ribbon containing semi-solid gel masses. The die is in the form of a soft gelatin capsule, which is then tumble-dried for about 20 to 60 minutes. The capsules are transferred to a tray, dried in a low-temperature / humidity drying chamber and dried until the capsules reach a shore hardness of at least 75. The capsules are then inspected, sorted, polished, printed The bottle is then affixed with a label containing prescription information. Alternatively, the bottle may be boxed with a package insert containing prescription information.

Example 2

Experiments were conducted to determine the formation of micelles in two compositions (A and B) as shown in Table 2. Both compositions containing omega-3 fatty acid ethyl ester were prepared as described in Example 1, and the omega-3 fatty acid ethyl ester had increased absorption and the food effect was substantially eliminated.

ingredient % (wt / wt) Composition A Composition B Omega-3 fatty acid ethyl ester 68.57 75.0 Polysorbate 80, NF 30.71 20.0 Pluronic F87 0.71 5.0 The formulated surfactant HLB 15.3 16.8 Total product HLB 13 13.2

The compositions that formed the well dispersed micelles generally had a surfactant HLB value of about 15 to about 17 formulated

Other compositions having a polysorbate 80 level of 27 to 29% with about 7% to about 22% pluronic F87 generally formed large oily globules. These compositions had a combined surfactant HLB value of about 17 to about 19. Based on these experiments, the total product HLB was from about 13 to about 14.4 and the combined surfactant HLB was from about 12 to about 17.

Example 3

Compositions A and B (1,000 mg) as shown in Table 2 were prepared by dissolving water (1 mg) in 0.1 N HCl, under USP dissolution 2 conditions, as described in USP (34 / National / Was added to a separate vessel containing 500 to 900 mL and observed. No composition was stirred or sheared. When observed under a microscope, very small and well-dispersed micelles could be seen. The micelles were stable at room temperature for more than 12 months and there was no discernible separation of omega-3 fatty acid esters from other components of the composition. Thus, a composition comprising between 0.7 and 5% pluronic F87 with 20 to 31% polysorbate 80 levels formed stable micelles.

Example 4

("Standard composition") representative of currently marketed drugs and nutritional Omega-3 products by ingesting Composition A ("Experimental composition") of Example 2 and performing blood monitoring, ), The increase in the absorption of the omega-3 fatty acid ethyl ester was measured. Standard compositions were prepared by encapsulating omega-3 ethyl esters using standard encapsulation methods. The absorption of omega-3 fatty acid ethyl ester was measured by comparing the Omega Index changes of the subjects after ingestion of the composition, as measured using an Omega Index (OmegaIndex) test kit by OmegaQuant. Before taking the composition, blood samples were taken from the subject and the baseline omega index of the subject was measured. The subjects then ingested soft gel capsules containing experimental or standard compositions. Four hours after ingestion, the following blood collection was performed. Subjects were fasting until 4 hours of blood collection from the initial baseline blood collection. The results are shown in Table 4.

Capsule composition Dose Omega Index EPA + DHA
Ethyl ester Early 4 hours increase Standard composition 1.52 g 5.2 5.3 1.92% Experimental composition
- Dose A
(4 capsules, 400 mg total capsule weight per capsule) 1.46 g 5.4 5.7 5.55% Experimental composition
- Dose B
(10 capsules, 400 mg total capsule weight per capsule) 3.65 g 4.9 5.3 8.16%

Example 5

Open-concept, open-label, randomized, triple arm parallel group demonstration was performed to show that in high triglyceride subjects with serum TG of 250 to 500 mg / dL when administered in fasting state, 1100 mg of SC401 capsules (Prepared as described in Example 1) versus 1000 mg of LOVAZA (omega-3 acid ethyl ester) capsule versus placebo (PLACEBO).

The aim of this study was to evaluate the efficacy of SC401 versus LOVAZA versus placebo for TG reductions over 14 days of treatment. Forty subjects were enrolled in this study to achieve at least 12 subjects in each of the three treatment arms.

Subjects were selected for this study using the following inclusion and exclusion criteria:

Include by:

· Men and women over 18 years of age.

200-500 mg / dL of serum TG.

· Normal health and good health condition based on medical history, simple physical examination, electrocardiogram and routine laboratory tests.

· Not being overweight or underweight for height according to attached height / weight table values (see attached height / weight chart).

· Agreement based on written notice is provided.

If the woman is able to return, an acceptable contraceptive is performed during the study period as determined by the investigator (s), eg condom, foam, jelly, diaphragm, intrauterine contraceptive device (IUD), or abstinence; Or the menstrual period has been abolished for more than one year; Or surgical infertility (bilateral tubal ligation, bilateral ovariectomy, or hysterectomy).

Exclusion criteria:

Severe hypertriglyceridemia (serum TG> 500 mg / dL).

· Intolerance to omega-3 or fish

Use Omega-3 fish oil, other EPA or DHA and / or DHA fortified foods or other TG-lowering drugs within 3 months of the initial study drug study or study period.

· Any fish consumption within 7 days of the initial study drug study or during the study

· Recent history of certain heart, kidney, liver, lung or gastrointestinal disorders or cancer (other than non-melanoma skin cancer).

· Diabetes or insulin therapy.

· Pregnant or lactating women. A woman who is not able to use medically approved contraceptive methods.

Use of certain types of hormones, anticonvulsants, immune drugs, antibiotics, antifungal and antiviral drugs and cardiac drugs.

· Warfarin (Coomadin) is used.

· Recent history of substance abuse or alcohol abuse (past 12 months).

· Exposure to any investigational product within 28 days before study drug administration.

Subjects who were diagnosed with the following conditions:

· Endocrine diabetes mellitus, hypothyroidism, pregnancy;

• hypertrophic hypertrophy, alcohol use;

Kidney disease, chronic kidney failure;

· Bile secretion, liver disease, hepatocellular dysfunction;

Immunoglobulin hyperparaproteinemia;

Ventilation;

· Any other condition that the investigator believes will interfere with the ability of the patient to provide informed consent and adhere to the study directions, to confuse the interpretation of the study results, or to put the patient at an excessive risk; And subjects with the following medications: thiazide diuretics, steroid hormones, microsomal enzymes, retinoic acid derivatives, protease inhibitors (HIV infection).

Before the specific procedure of the study, the applicant read and signed an informed consent document (ICD). In addition, the following tests were performed at the clinic for each period.

· Urine test for substance abuse, including cocaine, cannabis, amphetamine, barbiturate, benzodiazepine, and opiates. If the results were positive for these drugs, the subjects could be rejected / canceled from the study,

· Alcohol breathing test - If the result is positive for alcohol, reject the subject from the study / cancel,

· (For female subjects only) Urine pregnancy test (HCG) - If the result is positive for pregnancy,

· (For female subjects only) Adverse Events & Breast Examination - Refusal / cancellation of the subject from the study if there is any abnormality in the investigation.

The subjects were admitted to the medical institution for at least 48 hours prior to dosing for at least 14 days and asked the institution to stay for 16 consecutive nights.

Subjects were fasted for at least 10 hours prior to the morning dosing and the caffeine and / or xanthine containing products (ie, carbonated water, including caffeine, chocolate and caffeine - including alcohol, and cola), alcohols and vitamins (Including vitamin C and ascorbic acid and grape and its juices). No citrus juices, including orange juice and grape juice, were provided during the study.

After 10 hours of fasting, the subjects were administered monochromatic or low light conditions as follows:

SC401 (Omega-3 Fatty Acid Ethyl Ester, 1100 mg) Two capsules (as a single dose) were taken when woken up (taken with water only in the beaker at least 2 hours before breakfast) (Either at dinner and only with water for at least 2 hours, not taking any food or liquid during the following night)

LOVAZA® (Omega-3 Fatty Acid Ethyl Ester, 1000 mg, GlaxoSmithKline, RTP, NC 2770) Two capsules (as a single dose) when woken up (at least 2 hours before breakfast, After two capsules (as a single dose) are taken before sleeping (after dinner and at least two hours later with just water, without any food or liquids overnight)

Two capsules (as a single dose) were taken (as a single dose) after ingestion (at least 2 hours before breakfast, with only water in the beaker), placebo (ethyl oleate, 1000 mg capsules) (Before dinner and at least 2 hours after ingestion with water only, without any food or liquid ingestion during the night).

The amounts of omega-3 fatty acid ethyl esters, including Lovaza, SC401 and placebo, are shown in Table 5 below:

Capsule filling composition (mg) SC401 Lovaza ^® Placebo Total omega-3 fatty acid ethyl ester 754.3 934 0 - EPA ethyl ester 392.2 482 0 - DHA ethyl ester 165.9 370 0 Polysorbate 80, NF 337.9 0 0 Pluronic F87 7.8 0 0 Ethyl oleate 0 0 1000

Four blood samples (8 mL each) were collected over the study period. Blood samples will be collected in a plain vacuum tube by direct venipuncture at T _s , T ₀ , T _7d , T _14d . Vacuum lasers were placed vertically on a shelf placed in a humid ice bath until delivered to the diagnostic department.

_{T s, T 0, T 7d} , T 14d, 3 groups were measured fasting triglyceride / HDL / LDL / total cholesterol / non -HDL / level for each patient at each for.

The data are shown in Table 6 below:

Results from day 14 from baseline * SC401 Lovaza ^® Placebo Serum levels of triglyceride -48.5% -29.4% -27.7% * SC401 results adjusted to match the total amount of EPA and DHA ethyl ester administered with the Lovaza arm

Claims (121)

1. A pharmaceutical composition comprising at least one omega-3 fatty acid ester and at least one surfactant,
Wherein the at least one omega-3 fatty acid ester comprises at least about 40% (wt / wt) of the composition, and wherein the composition does not comprise omega-3 free fatty acids. The method according to claim 1,
Wherein said at least one omega-3 fatty acid ester is selected from the group consisting of hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosa-pentanoic acid, Enoic acid, tetraco-pentanoic acid, tetracohexaenoic acid, or a combination thereof. The method according to claim 1,
Wherein said at least one omega-3 fatty acid ester is substantially pure. The method according to claim 1,
Wherein the at least one omega-3 fatty acid ester is an ethyl ester. 5. The method of claim 4,
Wherein the at least one ethyl ester comprises a mixture of EPA and DHA ethyl ester, wherein the ratio of EPA: DHA is greater than 2: 1 to 3.4: 1, and wherein the combined EPA and DHA ethyl ester comprises about 40% wt / wt) to about 85% (wt / wt). The method of claim 3,
Wherein the combined EPA and DHA ethyl esters comprise about 50% (wt / wt) of the composition. The method of claim 3,
Wherein the at least one ethyl ester comprises a mixture of EPA and DHA ethyl ester, the ratio of EPA: DHA is about 2.4: 1, and the combined EPA and DHA ethyl ester is between about 40% (wt / wt) About 85% (wt / wt). 8. The method of claim 7,
Wherein the combined EPA and DHA ethyl esters comprise about 50% (wt / wt) of the composition. The method according to claim 1,
Wherein the at least one surfactant has a hydrophilic-lipophilic balance of at least 8.0. The method according to claim 1,
Wherein the at least one surfactant is selected from the group consisting of at least one anionic surfactant, at least one non-ionic surfactant, at least one zwitterionic surfactant, at least one cationic surfactant, or any combination thereof. The method according to claim 1,
Wherein the at least one surfactant comprises at least one non-ionic surfactant selected from the group consisting of one or more polysorbates, one or more poloxamers, or any combination thereof. The method according to claim 1,
Wherein the at least one surfactant comprises at least about 15% wt / wt to about 31% wt / wt of one or more polysorbates of the composition. The method according to claim 1,
Wherein the at least one surfactant is polysorbate 80. The method according to claim 1,
Wherein the at least one surfactant comprises from about 0.5% wt / wt to about 5% wt / wt of at least one poloxamer of the composition. The method according to claim 1,
&Lt; / RTI &gt; further comprising at least one antioxidant. The method according to claim 1,
At least one antioxidant selected from the group consisting of at least one tocopherol, at least one tocotrienol, or any combination thereof. The method according to claim 1,
Wherein the composition further comprises at least one tocopherol. The method according to claim 1,
Wherein the composition further comprises from about 0.01% (wt / wt) to about 5% (wt / wt) of one or more tocopherols. The method according to claim 1,
At least one terpene. The method according to claim 1,
Wherein the composition further comprises substantially pure d-limonene. The method according to claim 1,
Wherein the composition further comprises from about 0.1% (wt / wt) to about 5% (wt / wt) substantially pure d-limonene of the composition. The method according to claim 1,
Wherein the composition further comprises from about 0.1% (wt / wt) to about 5% (wt / wt) of a natural orange oil of the composition. The method according to claim 1,
Wherein the composition forms micelles in an aqueous medium. The composition of claim 1, wherein the composition forms micelles in an aqueous medium at an acidic pH. The method according to claim 1,
Wherein said composition forms micelles in 0.1 N HCl. 25. The method of claim 24,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. 26. The method of claim 25,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. 27. The method of claim 26,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. The method according to claim 1,
Wherein said composition is administered to a human subject in need of such administration with or without food. The method according to claim 1,
Wherein the at least one omega-3 fatty acid ester essentially consists of ethyl esters. 22. The method of claim 21,
Wherein said composition is administered to a human subject having a serum TG level of greater than or equal to about 155 mg per dL of serum, thereby reducing the subject's TG level by at least about 20%. From about 2: 1 to about 3.4: 1 EPA and DHA ethyl ester, from about 15% to about 31% polysorbate 80 and from about 0.5% (wt / wt) to about 5% (wt / wt) A mixed omega-3 fatty acid ester pharmaceutical composition comprising Lonic F87,
Wherein the omega-3 fatty acid ester comprises at least about 50% (wt / wt) of the composition, and wherein the composition does not comprise omega-3 free fatty acids. 33. The method of claim 32,
At least one antioxidant selected from the group consisting of at least one tocopherol, at least one tocotrienol, or any combination thereof. 33. The method of claim 32,
Wherein the composition further comprises at least one tocopherol. 33. The method of claim 32,
Wherein the composition further comprises from about 0.01% (wt / wt) to about 5% (wt / wt) of one or more tocopherols. 33. The method of claim 32,
At least one terpene. 33. The method of claim 32,
Wherein the composition further comprises substantially pure d-limonene. 33. The method of claim 32,
Wherein the composition further comprises from about 0.1% (wt / wt) to about 5% (wt / wt) substantially pure d-limonene of the composition. 33. The method of claim 32,
Wherein the composition further comprises from about 0.1% (wt / wt) to about 5% (wt / wt) of a natural orange oil of the composition. 33. The method of claim 32,
Wherein the composition forms micelles in an aqueous medium. 33. The method of claim 32,
Wherein the composition forms micelles in an aqueous medium at an acidic pH. 33. The method of claim 32,
Wherein said composition forms micelles in 0.1 N HCl. 41. The method of claim 40,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. 42. The method of claim 41,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. 43. The method of claim 42,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. 39. The method of claim 38,
Wherein said composition is administered to a human subject having a serum TG level greater than or equal to 155 mg TG per dL of serum, thereby reducing the TG level of said subject by at least about 20%. 33. The method of claim 32,
Wherein the composition is substantially independent of a food effect when administered to a human subject. 33. The method of claim 32,
EPA and DHA ethyl esters. CLAIMS 1. A method of treating the condition or disorder in a subject in need of such treatment,
Comprising administering to said subject a therapeutically effective amount of a composition comprising at least one omega-3 fatty acid ester and at least one surfactant,
Wherein said at least one omega-3 fatty acid ester occupies at least about 40% (wt / wt) of said composition, and wherein said composition does not comprise omega-3 free fatty acids. 50. The method of claim 49,
Wherein said at least one omega-3 fatty acid ester is selected from the group consisting of hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosa-pentanoic acid, Enoic acid, tetraco-pentanoic acid, tetracohexaenoic acid, or a combination thereof. 50. The method of claim 49,
Wherein said at least one omega-3 fatty acid ester is an ethyl ester. 50. The method of claim 49,
Wherein the at least one ethyl ester comprises a mixture of EPA and DHA ethyl ester, wherein the ratio of EPA: DHA is greater than 2: 1 to 3.4: 1, and wherein the combined EPA and DHA ethyl ester comprises about 40% wt / wt) to about 85% (wt / wt). 50. The method of claim 49,
Wherein the combined EPA and DHA ethyl esters comprise about 50% (wt / wt) of the composition. 50. The method of claim 49,
Wherein the at least one omega-3 fatty acid ethyl ester comprises a mixture of EPA and DHA ethyl ester, wherein the ratio of EPA: DHA is about 2.4: 1 and the combined EPA and DHA ethyl ester comprises about 40% / wt) to about 85% (wt / wt). 55. The method of claim 54,
Wherein the combined EPA and DHA ethyl esters comprise about 50% (wt / wt) of the composition. 50. The method of claim 49,
Wherein the at least one surfactant has a hydrophilic-lipophilic balance of 8.0 or greater. 50. The method of claim 49,
Wherein the at least one surfactant is selected from the group consisting of one or more anionic surfactants, one or more non-ionic surfactants, one or more zwitterionic surfactants, one or more cationic surfactants, or combinations thereof. 50. The method of claim 49,
Wherein the at least one surfactant comprises at least one non-ionic surfactant selected from the group consisting of one or more polysorbates, one or more poloxamers, or combinations thereof. 50. The method of claim 49,
Wherein the at least one surfactant comprises at least about 15% wt / wt to about 31% wt / wt of one or more polysorbates of the composition. 50. The method of claim 49,
Wherein the at least one surface active agent is polysorbate 80. 50. The method of claim 49,
Wherein the at least one surfactant comprises from about 0.5% wt / wt to about 5% wt / wt of the composition of at least one poloxamer. 50. The method of claim 49,
RTI ID = 0.0 &gt; antioxidant &lt; / RTI &gt; 50. The method of claim 49,
At least one tocopherol, at least one tocotrienol, and combinations thereof. 50. The method of claim 49,
RTI ID = 0.0 &gt; tocopherol. &Lt; / RTI &gt; 50. The method of claim 49,
Wherein the composition further comprises from about 0.01% (wt / wt) to about 5% (wt / wt) of one or more tocopherols of the composition. 50. The method of claim 49,
&Lt; / RTI &gt; further comprising at least one terpene. 50. The method of claim 49,
RTI ID = 0.0 &gt; d-limonene. &Lt; / RTI &gt; 50. The method of claim 49,
Wherein the composition further comprises from about 0.1% (wt / wt) to about 5% (wt / wt) substantially pure d-limonene of the composition. 50. The method of claim 49,
Further comprising from about 0.1% (wt / wt) to about 5% (wt / wt) of a natural orange oil of said composition. 50. The method of claim 49,
Wherein said composition forms micelles in an aqueous medium. 50. The method of claim 49,
Wherein said composition forms micelles in an aqueous medium at an acidic pH. 50. The method of claim 49,
Wherein said composition forms micelles in 0.1 N HCl. 71. The method of claim 70,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. 72. The method of claim 71,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. 73. The method of claim 72,
Wherein the micelle has a diameter of about 1 [mu] m to about 10 [mu] m. 49. The method of claim 47,
Wherein said composition is administered to a human subject with or without food. 50. The method of claim 49,
Wherein said at least one omega-3 fatty acid ester essentially consists of one or more ethyl esters. 50. The method of claim 49,
Wherein said cardiovascular condition or disorder is selected from the group consisting of hypertension, hyperlipidemia, hypertriglyceridemia, atherosclerosis, transient ischemic attack, systolic dysfunction, diastolic dysfunction, aneurysm, aortic dissection, myocardial ischemia, acute myocardial infarction (AMI) Acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), angina pectoris, unstable angina pectoris (UA), stable angina pectoris (SA), myocardial infarction, congestive heart failure, Cardiomyopathy, pulmonary heart disease, arrhythmia, valvular heart disease, endocarditis, pulmonary embolism, venous thrombosis, peripheral vascular disease, and peripheral arterial disease. 50. The method of claim 49,
Wherein the cardiovascular condition or disorder is selected from the group consisting of hypertension, hyperlipidemia, and combinations thereof. 50. The method of claim 49,
Wherein the cardiovascular condition or disorder is selected from the group consisting of hypertension, hyperlipidemia, and combinations thereof. 50. The method of claim 49,
Wherein the cardiovascular condition or disorder is high triglycerideemia. 83. The method of claim 81,
Wherein the total amount of serum triglyceride (s) is reduced by at least 20% within about 30 days of administration of said composition to a human subject. 83. The method of claim 82,
Wherein the total concentration of serum low density lipoprotein (LDL) in the human subject's blood does not substantially increase within 30 days of administering the composition. 55. The method of claim 54,
Wherein the therapeutically effective amount of the composition comprises at least 0.5 g / day. 55. The method of claim 54,
Wherein the subject's serum has an omega-3 fatty acid ester concentration of about 20 nmol / mL or greater within about 4 hours of administration. 50. The method of claim 49,
Wherein the composition is administered orally to the subject. 50. The method of claim 49,
Wherein said composition is administered to a subject as a gel or liquid capsule. 50. The method of claim 49,
Wherein the composition is administered as a parenteral composition. 50. The method of claim 49,
Wherein said composition is administered to a human subject in combination with a non-omega-3 fatty acid ester lipid-lowering agent. 90. The method of claim 89,
Wherein said non-omega-3 fatty acid ester lipid-lowering agent is selected from the group consisting of cholesterol absorption inhibitors, bile acid sequestrants / resins, statins, niacin and derivatives, MTP inhibitors, fibrates and CETP inhibitors. 50. The method of claim 49,
Wherein said composition is administered to a human subject having a serum TG level greater than or equal to 155 mg TG per dL of serum, wherein said subject's TG level is reduced by at least about 20%. A kit comprising the composition of claim 1 in a package together with instructions for using the composition of claim 1 to treat cardiovascular conditions or disorders. 93. The method of claim 92,
Wherein the composition is present in the form of a blister pack or bottle-packaged gel or liquid capsule. 93. The method of claim 92,
Wherein the instructions comprise administering the composition with or without food. 93. The method of claim 92,
Wherein the instructions comprise administering the composition to a human subject having a serum TG level greater than or equal to 150 mg TG per dL with or without food. 32. A kit comprising the composition of claim 32 in a package together with instructions for using the composition of claim 32 to treat cardiovascular conditions or disorders. 96. The method of claim 96,
Wherein the composition is present in the form of a blister pack or bottle-packaged gel or liquid capsule. 96. The method of claim 96,
Wherein the instructions comprise administering the composition with or without food. 96. The method of claim 96,
Wherein the instructions comprise administering the composition to a human subject having a serum TG level greater than or equal to 150 mg TG per dL with or without food. A functional food comprising a pharmaceutical composition comprising an edible solid, and at least one omega-3 fatty acid ester and at least one surfactant,
Wherein the at least one omega-3 fatty acid ester comprises at least about 40% (wt / wt) of the composition, and wherein the composition is substantially free of omega-3 free fatty acids. A functional food comprising a pharmaceutical composition comprising an edible liquid, and at least one omega-3 fatty acid ester and at least one surfactant,
Wherein the at least one omega-3 fatty acid ester comprises at least about 40% (wt / wt) of the composition, and wherein the composition is substantially free of omega-3 free fatty acids. From about 15% (wt / wt) to about 31% (wt / wt) polysorbate 80 and from about 0.5% wt / wt) to about 5% (wt / wt) of pluronic F87,
Wherein said EPA and DHA ethyl ester comprises at least about 40% (wt / wt) of said composition, and wherein said composition is substantially free of omega-3 free fatty acids. And an EPA and DHA ethyl ester in a ratio of greater than 2: 1 to 3.4: 1, a polysorbate 80 of about 15% (wt / wt) to about 31% (wt / wt) to about 5% (wt / wt) of pluronic F87,
Wherein said EPA and DHA ethyl ester comprises at least about 40% (wt / wt) of said composition, and wherein said composition does not comprise omega-3 free fatty acids. A method of treating a subject suffering from cardiovascular disease or suffering from cardiovascular disease, comprising administering an effective amount of a functional food according to claim 100. A method for treating a subject suffering from cardiovascular disease or suffering from cardiovascular disease, comprising administering an effective amount of the functional food according to claim 101. A method for treating a subject suffering from cardiovascular disease or suffering from cardiovascular disease, comprising administering an effective amount of the functional food according to claim 102. A method of treating a subject suffering from cardiovascular disease or suffering from cardiovascular disease, comprising administering an effective amount of the functional food according to claim 103. A pharmaceutical composition comprising at least one EPA ester and at least one DHA ester in a weight to weight ratio of greater than 2: 1 to less than 3.4: 1 (EPA: DHA)
Wherein said at least one EPA ester and said at least one DHA ester comprise from about 40% to about 95% by weight of said composition, and wherein said composition does not comprise an active ingredient other than an omega-3 fatty acid ester. 108. The method of claim 108,
Wherein the composition further comprises at least one terpene. 108. The method of claim 108,
Wherein the composition further comprises from about 0.1% (wt / wt) to about 5% (wt / wt) substantially pure d-limonene of the composition. CLAIMS 1. A method of treating the condition or disorder in a subject in need of such treatment,
Comprising administering to said subject a therapeutically effective amount of a composition comprising at least one EPA ester and at least one DHA ester thereof in a weight to weight ratio of greater than 2: 1 to less than 3.4: 1 (EPA: DHA)
Wherein said at least one EPA ester and said at least one DHA ester formulated comprise from about 40% to about 95% by weight of said composition, said composition being substantially free of other active ingredients other than omega-3 fatty acid ester . 111. The method of claim 111,
Wherein the composition further comprises at least one terpene. 111. The method of claim 111,
Wherein the composition further comprises from about 0.1% (wt / wt) to about 5% (wt / wt) substantially pure d-limonene of the composition. 1. A pharmaceutical composition comprising at least one omega-3 fatty acid ester and at least one terpene,
Wherein said at least one omega-3 fatty acid ester comprises at least about 40% (wt / wt) of said composition and is substantially free of said at least one other omega-3 fatty acid ester. 115. The method of claim 114,
Wherein the at least one terpene is d-limonene. 115. The method of claim 114,
Wherein the at least one terpene is substantially pure d-limonene. 115. The method of claim 114,
Wherein the at least one terpene is more than 95% pure d-limonene. A composition comprising a mixture of EPA and DHA ethyl ester and at least one terpene,
Wherein the ratio of EPA to DHA is about 2.4: 1 and the combined EPA and DHA ethyl ester comprises about 40% (wt / wt) to about 95% (wt / wt) And no other active ingredients other than one or more terpenes. 121. The method of claim 118,
Wherein the at least one terpene is d-limonene. 121. The method of claim 118,
Wherein the at least one terpene is substantially pure d-limonene. 121. The method of claim 118,
Wherein said at least one terpene is at least 95% pure d-limonene.

Images